Quinazoline derivatives with anti-tumour activity

ABSTRACT

The invention concerns quinazoline derivatives of Formula I 
                 
 
wherein each of m, R 1 , n, R 2  and R 3  have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB01/04498, filed Oct. 9, 2001, whichclaims priority from European Patent Application No. 00402844.5, filedOct. 13, 2000, the specifications of each of which are incorporated byreference herein. International Application No. PCT/GB01/04498 waspublished under PCT Article 21(2) in English.

The invention concerns certain novel quinazoline derivatives, orpharmaceutically-acceptable salts thereof, which possess anti-tumouractivity and are accordingly useful in methods of treatment of the humanor animal body. The invention also concerns processes for themanufacture of said quinazoline derivatives, to pharmaceuticalcompositions containing them and to their use in therapeutic methods,for example in the manufacture of medicaments for use in the preventionor treatment of solid tumour disease in a warm-blooded animal such asman.

Many of the current treatment regimes for cell proliferation diseasessuch as psoriasis and cancer utilise compounds which inhibit DNAsynthesis. Such compounds are toxic to cells generally but their toxiceffect on rapidly dividing cells such as tumour cells can be beneficial.Alternative approaches to anti-tumour agents which act by mechanismsother than the inhibition of DNA synthesis have the potential to displayenhanced selectivity of action.

In recent years it has been discovered that a cell may become cancerousby virtue of the transformation of a portion of its DNA into an oncogenei.e. a gene which, on activation, leads to the formation of malignanttumour cells (Bradshaw, Mutagenesis, 1986, 1, 91). Several suchoncogenes give rise to the production of peptides which are receptorsfor growth factors. Activation of the growth factor receptor complexsubsequently leads to an increase in cell proliferation. It is known,for example, that several oncogenes encode tyrosine kinase enzymes andthat certain growth factor receptors are also tyrosine kinase enzymes(Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsen et al., Ann.Reports in Med. Chem., 1989, Chpt. 13). The first group of tyrosinekinases to be identified arose from such viral oncogenes, for examplepp60^(v-Src) tyrosine kinase (otherwise known as v-Src), and thecorresponding tyrosine kinases in normal cells, for example pp60^(c-Src)tyrosine kinase (otherwise known as c-Src).

Receptor tyrosine kinases are important in the transmission ofbiochemical signals which initiate cell replication. They are largeenzymes which span the cell membrane and possess an extracellularbinding domain for growth factors such as epidermal growth factor (EGF)and an intracellular portion which functions as a kinase tophosphorylate tyrosine amino acids in proteins and hence to influencecell proliferation. Various classes of receptor tyrosine kinases areknown (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based onfamilies of growth factors which bind to different receptor tyrosinekinases. The classification includes Class I receptor tyrosine kinasescomprising the EGF family of receptor tyrosine kinases such as the EGF,TGFα, Neu and erbB receptors, Class II receptor tyrosine kinasescomprising the insulin family of receptor tyrosine kinases such as theinsulin and IGFI receptors and insulin-related receptor (IRR) and ClassIII receptor tyrosine kinases comprising the platelet-derived growthfactor (PDGF) family of receptor tyrosine kinases such as the PDGFα,PDGFβ and colony-stimulating factor 1 (CSF1) receptors.

It is also known that certain tyrosine kinases belong to the class ofnon-receptor tyrosine kinases which are located intracellularly and areinvolved in the transmission of biochemical signals such as those thatinfluence tumour cell motility, dissemination and invasiveness andsubsequently metastatic tumour growth (Ullrich et al., Cell, 1990, 61,203-212, Bolen et al., FASEB J., 1992, 6; 3403-3409, Brickell et al.,Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al.,Oncogene, 1993, 8, 2025-2031, Courtneidge et al., Semin. Cancer Biol.,1994, 5, 239-246, Lauffenburger et al., Cell, 1996, 84, 359-369, Hankset al., BioEssays, 1996, 19, 137-145, Parsons et al., Current Opinion inCell Biology, 1997, 9, 187-192, Brown et al., Biochimica et BiophysicaActa, 1996, 1287, 121-149 and Schlaepfer et al., Progress in Biophysicsand Molecular Biology, 1999, 71, 435-478). Various classes ofnon-receptor tyrosine kinases are known including the Src family such asthe Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl andArg and the Jak family such as Jak 1 and Tyk 2.

It is known that the Src family of non-receptor tyrosine kinases arehighly regulated in normal cells and in the absence of extracellularstimuli are maintained in an inactive conformation. However, some Srcfamily members, for example c-Src tyrosine kinase, is frequentlysignificantly activated (when compared to normal cell levels) in commonhuman cancers such as gastrointestinal cancer, for example colon, rectaland stomach cancer (Cartwright et al., Proc. Natl. Acad. Sci. USA, 1990,87, 558-562 and Mao et al., Oncogene, 1997, 15, 3083-3090), and breastcancer (Muthuswamy et al., Oncogene, 1995, 11, 1801-1810). The Srcfamily of non-receptor tyrosine kinases has also been located in othercommon human cancers such as non-small cell lung cancers (NSCLCs)including adenocarcinomas and squamous cell cancer of the lung(Mazurenko et al., European Journal of Cancer, 1992, 28, 372-7), bladdercancer (Fanning et al., Cancer Research, 1992, 52, 1457-62), oesophagealcancer (Jankowski et al., Gut, 1992, 33, 1033-8), cancer of theprostate, ovarian cancer (Wiener et al., Clin. Cancer Research, 1999, 5,2164-70) and pancreatic cancer (Lutz et al., Biochem. and Biophys. Res.Comm., 1998, 243, 503-8). As further human tumour tissues are tested forthe Src family of non-receptor tyrosine kinases it is expected that itswidespread prevalence will be established.

It is further known that the predominant role of c-Src non-receptortyrosine kinase is to regulate the assembly of focal adhesion complexesthrough interaction with a number of cytoplasmic proteins including, forexample, focal adhesion kinase and paxillin. In addition c-Src iscoupled to signalling pathways that regulate the actin cytoskeletonwhich facilitates cell motility. Likewise, important roles are played bythe c-Src, c-Yes and c-Fyn non-receptor tyrosine kinases in integrinmediated signalling and in disrupting cadherin-dependent cell-celljunctions (Owens et al., Molecular Biology of the Cell, 2000, 11, 51-64and Klinghoffer et al., EMBO Journal, 1999, 18, 2459-2471). Cellularmotility is necessarily required for a localised tumour to progressthrough the stages of dissemination into the blood stream, invasion ofother tissues and initiation of metastatic tumour growth. For example,colon tumour progression from localised to disseminated, invasivemetastatic disease has been correlated with c-Src non-receptor tyrosinekinase activity (Brunton et al., Oncogene, 1997, 14, 283-293, Fincham etal., EMBO J, 1998, 17, 81-92 and Verbeek et al., Exp. Cell Research,1999, 248, 531-537).

Accordingly it has been recognised that an inhibitor of suchnon-receptor tyrosine kinases should be of value as a selectiveinhibitor of the motility of tumour cells and as a selective inhibitorof the dissemination and invasiveness of mammalian cancer cells leadingto inhibition of metastatic tumour growth. In particular an inhibitor ofsuch non-receptor tyrosine kinases should be of value as ananti-invasive agent for use in the containment and/or treatment of solidtumour disease.

We have now found that surprisingly certain quinazoline derivativespossess potent anti-tumour activity. Without wishing to imply that thecompounds disclosed in the present invention possess pharmacologicalactivity only by virtue of an effect on a single biological process, itis believed that the compounds provide an anti-tumour effect by way ofinhibition of one or more of the non-receptor tyrosine-specific proteinkinases that are involved in the signal transduction steps which lead tothe invasiveness and migratory ability of metastasising tumour cells. Inparticular, it is believed that the compounds of the present inventionprovide an anti-tumour effect by way of inhibition of the Src family ofnon-receptor tyrosine kinases, for example by inhibition of one or moreof c-Src, c-Yes and c-Fyn.

It is also known that c-Src non-receptor tyrosine kinase enzyme isinvolved in the control of osteoclast-driven bone resorption (Soriano etal., Cell, 1991, 64, 693-702; Boyce et al., J. Clin. Invest., 1992, 90,1622-1627; Yoneda et al., J. Clin. Invest., 1993, 91, 2791-2795 andMissbach et al., Bone, 1999, 24, 437-49). An inhibitor of c-Srcnon-receptor tyrosine kinase is therefore of value in the prevention andtreatment of bone diseases such as osteoporosis, Paget's disease,metastatic disease in bone and tumour-induced hypercalcaemia.

The compounds of the present invention are also useful in inhibiting theuncontrolled cellular proliferation which arises from variousnon-malignant diseases such as inflammatory diseases (for examplerheumatoid arthritis and inflammatory bowel disease), fibrotic diseases(for example hepatic cirrhosis and lung fibrosis), glomerulonephritis,multiple sclerosis, psoriasis, hypersensitivity reactions of the skin,blood vessel diseases (for example atherosclerosis and restenosis),allergic asthma, insulin-dependent diabetes, diabetic retinopathy anddiabetic nephropathy.

Generally the compounds of the present invention possess potentinhibitory activity against the Src family of non-receptor tyrosinekinases, for example by inhibition of c-Src and/or c-Yes, whilstpossessing less potent inhibitory activity against other tyrosine kinaseenzymes such as the receptor tyrosine kinases, for example EGF receptortyrosine kinase and/or VEGF receptor tyrosine kinase. Furthermore,certain compounds of the present invention possess substantially betterpotency against the Src family of non-receptor tyrosine kinases, forexample c-Src and/or c-Yes, than against VEGF receptor tyrosine kinase.Such compounds possess sufficient potency against the Src family ofnon-receptor tyrosine kinases, for example c-Src and/or c-Yes, that theymay be used in an amount sufficient to inhibit, for example, c-Srcand/or c-Yes whilst demonstrating little activity against VEGF receptortyrosine kinase.

According to one aspect of the invention there is provided a quinazolinederivative of the Formula I

wherein m is 0, 1, 2 or 3;

each R¹ group, which may be the same or different, is selected fromhalogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto,amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:Q¹—X¹—wherein X¹ is a direct bond or is selected from O, S, SO, SO₂, N(R⁴),CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂, SC(R⁴)₂ andN(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or (1-6C)alkyl, and Q¹ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or(R¹)_(m) is (1-3C)alkylenedioxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R⁵), CO, CH(OR⁵), CON(R⁵),N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡C wherein R⁵ is hydrogen or(1-6C)alkyl or, when the inserted group is N(R⁵), R⁵ may also be(2-6C)alkanoyl,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:Q²—X²—wherein X² is a direct bond or is selected from CO and N(R⁶)CO, whereinR⁶ is hydrogen or (1-6C)alkyl, and Q² is aryl, aryl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoyN-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:—X³—Q³wherein X³ is a direct bond or is selected from O, S, SO, SO₂, N(R⁷),CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O, C(R⁷)₂S andN(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1-6C)alkyl, and Q³ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:—X⁵—Q⁴wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁴ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo or thioxo substituents;

R² is hydrogen or (1-6C)alkyl;

n is 0, 1, 2 or 3; and

R³ is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:—X⁶—R¹¹wherein X⁶ is a direct bond or is selected from O and N(R¹²), whereinR¹² is hydrogen or (1-6C)alkyl, and R¹¹ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula: —X⁷—Q⁵wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂, N(R¹³),CO, CH(OR¹³), CON(R¹³), N(R¹³)CO, SO₂N(R¹³), N(R¹³)SO₂, C(R¹³)₂O,C(R¹³)₂S and N(R¹³)C(R¹³)₂, wherein R¹³ is hydrogen or (1-6C)alkyl, andQ⁵ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2substituents, which may be the same or different, selected fromhalogeno, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy,and any heterocyclyl group within Q⁵ optionally bears 1 or 2 oxo orthioxo substituents, or a pharmaceutically-acceptable salt thereof.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups such as propyl, isopropyland tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However referencesto individual alkyl groups such as “propyl” are specific for thestraight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only and references to individual cycloalkyl groups such as“cyclopentyl” are specific for that 5-membered ring only. An analogousconvention applies to other generic terms, for example (1-6C)alkoxyincludes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy,(1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino andcyclohexylamino, and di-[(1-6Calkyl]amino includes dimethylamino,diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the above-mentioned activity. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the above-mentioned activity may be evaluated using the standardlaboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁵) when it isaryl or for the aryl group within a ‘Q’ group is, for example, phenyl ornaphthyl, preferably phenyl.

A suitable value for any one of the ‘Q’ groups (Q¹ or Q³) when it is(3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a ‘Q’ groupis, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one ofthe ‘Q’ groups (Q¹ or Q³) when it is (3-7C)cycloalkenyl or for the(3-7C)cycloalkenyl group within a ‘Q’ group is, for example,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁵) when it isheteroaryl or for the heteroaryl group within a ‘Q’ group is, forexample, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms selected fromoxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,cinnolinyl or naphthyridinyl.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁵) when it isheterocyclyl or for the heterocyclyl group within a ‘Q’ group is, forexample, a non-aromatic saturated or partially saturated 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulphur, for example oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, pyrrolinyl,pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyrimidinyl, preferablytetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl,1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl. Asuitable value for such a group which bears 1 or 2 oxo or thioxosubstituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for a ‘Q’ group when it is heteroaryl-(1-6C)alkyl is,for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.The invention comprises corresponding suitable values for ‘Q’ groupswhen, for example, rather than a heteroaryl-(1-6C)alkyl group, anaryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl group ispresent.

In structural Formula I there is a hydrogen atom at each of the 2- and5-positions on the quinazoline ring. It is to be understood thereby thatthe R¹ substituents may only be located at the 6-, 7- or 8-positions onthe quinazoline ring i.e. that the 2- and 5-positions remainunsubstituted. It is further to be understood that the R³ group that maybe present on the benzofuran ring within structural Formula I may belocated on the phenyl ring or on the carbon atoms within the furyl ring.

Suitable values for any of the ‘R’ groups (R¹ to R¹³) or for variousgroups within an R¹ or R³ substituent include:

for halogeno fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl,ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl,isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl,2-propynyl and but-2-ynyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy,isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for(2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio:methylthio, ethylthio and propylthio; for (1-6C)alkylsulphinyl:methylsulphinyl and ethylsulphinyl; for (1-6C)alkylsulphonyl:methylsulphonyl and ethylsulphonyl; for (1-6C)alkylamino: methylamino,ethylamino, propylamino, isopropylamino and butylamino; fordi-[(1-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino; for (1-6C)alkoxycarbonyl:methoxycarbonyl, ethoxycarbonyl, propoxy- carbonyl andtert-butoxycarbonyl; for N-(1-6C)alkyl- N-methylcarbamoyl,N-ethylcarbamoyl and carbamoyl: N-propylcarbamoyl; for N,N-di-[(1-N,N-dimethylcarbamoyl, N-ethyl- 6C)alkyl]carbamoyl: N-methylcarbamoyland N,N-diethyl- carbamoyl; for (2-6C)alkanoyl: acetyl and propionyl;for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for(2-6C)alkanoylamino: acetamido and propionamido; for N-(1-6C)alkyl-(2-N-methylacetamido and N-methylpropion- 6C)alkanoylamino: amido; forN-(1-6C)alkyl- N-methylsulphamoyl and N-ethyl- sulphamoyl: sulphamoyl;for N,N-di-[(1- N-dimethylsulphamoyl; 6C)alkyl]sulphamoyl: for(1-6C)alkanesulphonyl- methanesulphonylamino and ethane- amino:sulphonylamino; for N-(1-6C)alkyl-(1- N-methylmethanesulphonylamino and6C)alkanesulphonylamino: N-methylethanesulphonylamino; for(3-6C)alkenoylamino: acrylamido, methacrylamido and croton- amido; forN-(1-6C)alkyl-(3- N-methylacrylamido and N-methylcroton-6C)alkenoylamino: amido; for (3-6C)alkynoylamino: propiolamido; forN-(1-6C)alkyl-(3- N-methylpropiolamido; 6C)alkynoylamino: foramino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-amino- ethyl and3-aminopropyl; for (1-6C)alkylamino-(1- methylaminomethyl,ethylaminomethyl, 6C)alkyl: 1-methylaminoethyl, 2-methylaminoethyl,2-ethylaminoethyl and 3-methylaminopropyl; for di-[(1-6C)alkyl]amino-dimethylaminomethyl, diethylaminomethyl, (1-6C)alkyl:1-dimethylaminoethyl, 2-dimethylamino- ethyl and 3-dimethylaminopropyl;for halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloro- ethyland 3-chloropropyl; for hydroxy-(1-6C)alkyl: hydroxymethyl,2-hydroxyethyl, 1-hydroxy- ethyl and 3-hydroxypropyl; for(1-6C)alkoxy-(1- methoxymethyl, ethoxymethyl, 1-methoxy- 6C)alkyl:ethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; forcyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyano- ethyl and3-cyanopropyl; for (2-6C)alkanoylamino- acetamidomethyl,propionamidomethyl and (1-6C)alkyl: 2-acetamidoethyl; and for(1-6C)alkoxycarbonyl- methoxycarbonylaminomethyl, amino-(1-6C)alkyl:ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and2-methoxycarbonylaminoethyl.

A suitable value for (R¹)_(m) when it is a (1-3C)alkylenedioxy group is,for example, methylenedioxy or ethylenedioxy and the oxygen atomsthereof occupy adjacent ring positions.

When, as defined hereinbefore, an R¹ group forms a group of the formulaQ¹—X¹— and, for example, X¹ is a OC(R⁴)₂ linking group, it is the carbonatom, not the oxygen atom, of the OC(R⁴)₂ linking group which isattached to the quinazoline ring and the oxygen atom is attached to theQ¹ group. Similarly, when, for example a CH₃ group within a R¹substituent bears a group of the formula —X³—Q³ and, for example, X³ isa C(R⁷)₂O linking group, it is the carbon atom, not the oxygen atom, ofthe C(R⁷)₂O linking group which is attached to the CH₃ group and theoxygen atom is linked to the Q³ group. A similar convention applies tothe attachment of the groups of the formulae Q²—X²— and —X⁷—Q⁵.

As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylenechain within a R¹ substituent may be optionally separated by theinsertion into the chain of a group such as O, CON(R⁵) or C≡C. Forexample, insertion of a C≡C group into the ethylene chain within a2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy groupand, for example, insertion of a CONH group into the ethylene chainwithin a 3-methoxypropoxy group gives rise to, for example, a2-(2-methoxyacetamido)ethoxy group.

When, as defined hereinbefore, any CH₂═CH— or HC≡C— group within a R¹substituent optionally bears at the terminal CH₂═ or HC≡ position asubstituent such as a group of the formula Q²—X²— wherein X² is, forexample, NHCO and Q² is a heterocyclyl-(1-6C)alkyl group, suitable R¹substituents so formed include, for example,N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylvinyl orN-[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylethynyl.

When, as defined hereinbefore, any CH₂ or CH₃ group within a R¹substituent optionally bears on each said CH₂ or CH₃ group one or morehalogeno or (1-6C)alkyl substituents, there are suitably 1 or 2 halogenoor (1-6C)alkyl substituents present on each said CH₂ group and there aresuitably 1, 2 or 3 such substituents present on each said CH₃ group.

When, as defined hereinbefore, any CH₂ or CH₃ group within a R¹substituent optionally bears on each said CH₂ or CH₃ group a substituentas defined hereinbefore, suitable R¹ substituents so formed include, forexample, hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy,hydroxy-substituted amino-(2-6C)alkoxy groups such as3-amino-2-hydroxypropoxy, hydroxy-substituted(1-6C)alkylamino-(2-6C)alkoxy groups such as2-hydroxy-3-methylaminopropoxy, hydroxy-substituteddi-[(1-6C)alkyl]amino-(2-6C)alkoxy groups such as3-dimethylamino-2-hydroxypropoxy, hydroxy-substitutedheterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,hydroxy-substituted amino-(2-6C)alkylamino groups such as3-amino-2-hydroxypropylamino, hydroxy-substituted(1-6C)alkylamino-(2-6C)alkylamino groups such as2-hydroxy-3-methylaminopropylamino, hydroxy-substituteddi-[(1-6C)alkyl]amino-(2-6C)alkylamino groups such as3-dimethylamino-2-hydroxypropylamino hydroxy-substituted (1-6C)alkoxygroups such as 2-hydroxyethoxy, (1-6C)alkoxy-substituted (1-6C)alkoxygroups such as 2-methoxyethoxy and 3-ethoxypropoxy,(1-6C)alkylsulphonyl-substituted (1-6C)alkoxy groups such as2-methylsulphonylethoxy and heterocyclyl-substituted(1-6C)alkylamino-(1-6C)alkyl groups such as2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula I,for example an acid-addition salt with an inorganic or organic acid suchas hydrochloric, hydrobromic, sulphulic, trifluoroacetic, citric ormaleic acid; or, for example, a salt of a compound of the Formula Iwhich is sufficiently acidic, for example an alkali or alkaline earthmetal salt such as a calcium or magnesium salt, or an ammonium salt, ora salt with an organic base such as methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example,quinazoline derivatives of the Formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of m, R¹, R², nand R³ has any of the meanings defined hereinbefore or in paragraphs (a)to (h) hereinafter:

-   (a) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from halogeno, trifluoromethyl, hydroxy,    amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,    (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,    N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,    (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,    (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,    (3-6C)alkynoylamino and N-(1-6C)alkyl-(3-6C)alkynoylamino, or from a    group of the formula:    Q¹—X¹—-    wherein X¹ is a direct bond or is selected from O, N(R⁴), CON(R⁴),    N(R⁴)CO and OC(R⁴)₂ wherein R⁴ is hydrogen or (1-6C)alkyl, and Q¹ is    aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl,    heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R⁵), CON(R⁵), N(R⁵)CO, CH═CH and C≡Cwherein R⁵ is hydrogen or (1-6C)alkyl, or, when the inserted group isN(R⁵), R⁵ may also be (2-6C)alkanoyl,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:Q²—X²—wherein X² is a direct bond or is CO or N(R⁶)CO, wherein R⁶ is hydrogenor (1-6C)alkyl, and Q² is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino andN-(1-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula:—X³—Q³wherein X³ is a direct bond or is selected from O, N(R⁶), CON(R⁷),N(R⁷)CO and C(R⁷)₂O, wherein R⁷ is hydrogen or (1-6C)alkyl, and Q³ isheteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1-6C)alkyl, and R⁸ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and from a group of the formula:—X⁵—Q⁴wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁴ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (b) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from fluoro, chloro, trifluoromethyl,    hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl,    ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino,    ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino,    N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido,    acrylamido and propiolamido, or from a group of the formula:    Q¹—X¹—-    wherein X¹ is a direct bond or is selected from O, NH, CONH, NHCO    and OCH₂ and Q¹ is phenyl, benzyl, cyclopropylmethyl, 2-thienyl,    1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 2-, 3- or    4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,    2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,    2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or    4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or    4-pyridyl)propyl, 1-, 2- or 3-pyrrolidinyl, morpholino,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,    piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,    homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,    morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,    3- or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,    2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,    4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,    4-morpholinobutyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-4yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,    2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,    2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,    2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,    2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,    4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, CONH, NHCO, CH═CH and C≡C,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl,3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, orfrom a group of the formula:Q²—X²—wherein X² is a direct bond or is CO, NHCO or N(Me)CO and Q² is pyridyl,pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl,2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino, dimethylamino,diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino,N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or froma group of the formula:—X³—Q³wherein X³ is a direct bond or is selected from O, NH, CONH, NHCO andCH₂O and Q³ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl, or optionally bears 1 substituent selected from agroup of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and NH and R⁸ is2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl,methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl ortert-butoxycarbonylaminomethyl, and from a group of the formula:—X⁵—Q⁴wherein X⁵ is a direct bond or is selected from O, NH and CO and Q⁴ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,each of which optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (c) m is 1 or 2 and each R¹ group, which may be the same or    different, is located at the 6- and/or 7-positions and is selected    from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino,    ethylamino, dimethylamino, diethylamino, acetamido, propionamido,    cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,    tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,    tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy,    3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy,    3-(1,2,3-triazol-1-yl)propoxy, 2-(1,2,4-triazol-1-yl)ethoxy,    3-(1,2,4-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,    pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy,    2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy,    3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino,    piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,    4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,    2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy,    2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,    2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,    piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,    piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,    3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,    3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,    3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,    2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy,    2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1-ylpropylamino,    4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino,    pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,    3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,    3-morpholinopropylamino, 4-morpholinobutylamino,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,    2-piperidinoethylamino, 3-piperidinopropylamino,    4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino,    piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino,    piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino,    2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,    2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,    4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or    3-homopiperazin-1-ylpropylamino,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, CH═CH and C≡C,

and when R¹ is a vinyl or ethynyl group, the R¹ substituent optionallybears at the terminal CH₂═ or HC≡ position a substituent selected fromN-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl,methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of theformula:

 Q²—X²—

wherein X² is a direct bond or is NHCO or N(Me)CO and Q² isimidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl,2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl,2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or4-piperazin-1-ylbutyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino, dimethylamino,diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino,N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido,

and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclylgroup within a substituent on R¹ optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and apyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl orhomopiperazin-1-yl group within a R¹ substituent is optionallyN-substituted with 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, the last 8 of which substituents each optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (d) m is 1 and the R¹ group is located at the 6- or 7-position and    is selected from hydroxy, amino, methyl, ethyl, propyl, butyl,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino,    ethylamino, dimethylamino, diethylamino, acetamido, propionamido,    benzyloxy, 2-imidazol-1-ylethoxy, 2-(1,2,3-triazol-1-yl)ethoxy,    2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,    3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy,    pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,    3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,    4-morpholinobutoxy,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,    2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,    piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,    2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,    2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,    3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy or    3-homopiperazin-1-ylpropoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino, dimethylamino,diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino andacetoxy,

and wherein any heteroaryl or heterocyclyl group; within a substituenton R¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (e) R² is hydrogen;-   (f) n is 1 or 2 and the R³ groups, which may be the same or    different, are located at the 5- and/or 6-positions of the    benzofuran ring and are selected from halogeno, trifluoromethyl,    cyano, hydroxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and    (1-6C)alkoxy;-   (g) n is 1 or 2 and the R³ groups, which may be the same or    different, are located at the 5- and/or 6-positions of the    benzofuran ring and are selected from fluoro, chloro, bromo, iodo,    trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,    isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy;    and-   (h) n is 0.

A preferred compound of the invention is a quinazoline derivative of theFormula I wherein:

m is 1 or 2 and each R¹ group, which may be the same or different, islocated at the 6- and/or 7-positions and is selected from hydroxy,amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino, dimethylamino,diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino,N-methyl-N-propylamino and acetoxy;

and wherein any heteroaryl or heterocyclyl group within a substituent onR¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R¹substituent is optionally N-substituted with 2-methoxyethyl,3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl,2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, thelast 8 of which substituents each optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro, methyland methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

R² is hydrogen;

n is 0 or 1 and the R³ group, if present, is located at the 5- or6-position of the benzofuran ring and is selected from fluoro, chloro,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl,methoxy and ethoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

m is 2 and the first R¹ group is located at the 6-position and isselected from hydroxy, methoxy, ethoxy and propoxy, and the second R¹group is located at the 7-position and is selected from2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy,2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy,2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy,4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,3-(N-isopropyl-N-methylamino)propoxy,4-(N-isopropyl-N-methylamino)butoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 4-morpholinobutoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy,piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy,3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy,2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,4-(4-methylpiperazin-1-yl)butoxy, 2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,4-(4-cyanomethylpiperazin-1-yl)butoxy,2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy, 2-methylsulphonylethoxy and3-methylsulphonylpropoxy,

and wherein any CH₂ group within the second R¹ group that is attached totwo carbon atoms optionally bears a hydroxy group or acetoxy group onsaid CH₂ group,

and wherein any heterocyclyl group within the second R¹ group optionallybears 1 or 2 oxo substituents;

R² is hydrogen; and

n is 0 or n is 1 and the R³ group is located at the 5- or 6-position ofthe benzofuran ring and is selected from fluoro, chloro,trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

m is 2 and the first R¹ group is located at the 6-position and isselected from hydroxy, methoxy, ethoxy and propoxy, and the second R¹group is located at the 7-position and is selected from2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylaminoethoxy,3-diethylaminopropoxy, 2-diisopropylaminoethoxy,3-diisopropylaminopropoxy, 2-(N-isopropyl-N-methylamino)ethoxy,3-(N-isopropyl-N-methylamino)propoxy,2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy,2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 3-homopiperidinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy and3-(4-cyanomethylpiperazin-1-yl)propoxy,

and wherein any CH₂ group within the second R¹ group that is attached totwo carbon atoms optionally bears a hydroxy group or acetoxy group onsaid CH₂ group,

R² is hydrogen; and

n is 0 or n is 1 or 2 and an R³ group, if present, is located at the 5-or 6-position of the benzofuran ring and is selected from fluoro,chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxyand ethoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from3-(N-isopropyl-N-methylamino)propoxy,3-(N-isobutyl-N-methylamino)propoxy, 3-pyrrolidin-1-ylpropoxy,3-morpholinopropoxy, 3-piperidinopropoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 3-homopiperidinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy and3-(4-cyanomethylpiperazin-1-yl)propoxy,

and wherein any CH₂ group within the second R¹ group that is attached totwo carbon atoms optionally bears a hydroxy or acetoxy group on said CH₂group;

R² is hydrogen; and

n is 0 or n is 1 and the R³ group is located at the 5- or 6-position ofthe benzofuran ring and is selected from fluoro and chloro;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from3-(N-isopropyl-N-methylamino)propoxy, 3-pyrrolidin-1-ylpropoxy,3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,3-piperidinopropoxy, N-methylpiperidin-4-ylmethoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy and2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy,

and wherein any CH₂ group within the second R¹ group that is attached totwo carbon atoms optionally bears a hydroxy group on said CH₂ group;

R² is hydrogen; and

n is 0;

or a pharmaceutically-acceptable acid-addition salt thereof.

A particular preferred compound of the invention is, for example, aquinazoline derivative of the Formula I selected from:

-   4-(7-benzofuranylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(7-benzofuranylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(7-benzofuranylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,-   4-(7-benzofuranylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline-   4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline-   4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(7-benzofuranylamino)-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline,-   7-(2-acetoxy-3-pyrrolidin-1-ylpropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,-   7-[2-acetoxy-3-(N-isopropyl-N-methylamino)propoxy]-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,-   7-[2-acetoxy-3-(4-cyanomethylpiperazin-1-yl)propoxy]-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,-   7-(2-acetoxy-3-piperidinopropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxyquinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6-methoxyquinazoline,-   4-(3-chlorobenzofuran-7-ylamino)-7-[3-(4-cyanomethylpiperazin-1-yl)-2-hydroxypropoxy]-6-methylaminazoline    and-   4-(3-chlorobenzofuran-7-ylamino)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxyquinazoline;    or a pharmaceutically-acceptable acid-addition salt thereof.

A quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a quinazoline derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, m, R¹, R², n and R³ have any of themeanings defined hereinbefore. Necessary starting materials may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

-   (a) The reaction of a quinazoline of the Formula II-    wherein L is a displaceable group and m and R¹ have any of the    meanings defined hereinbefore except that any functional group is    protected if necessary, with an aniline of the Formula III-    wherein R², n and R³ have any of the meanings defined hereinbefore    except that any functional group is protected if necessary,    whereafter any protecting group that is present is removed by    conventional means.

The reaction may conveniently be carried out in the presence of asuitable acid or in the presence of a suitable base. A suitable acid is,for example, an inorganic acid such as, for example, hydrogen chlorideor hydrogen bromide. A suitable base is, for example, an organic aminebase such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide, or, for example, an alkali metal hydride, forexample sodium hydride, or, for example, an alkali metal amide, forexample sodium amide or sodium 1,1,1,3,3,3-hexamethyldisilazide.

A suitable displaceable group L is, for example, a halogeno, alkoxy,aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, pentafluorophenoxy, methanesulphonyloxy ortoluene-4-sulphonyloxy group. The reaction is conveniently carried outin the presence of a suitable inert solvent or diluent, for example analcohol or ester such as methanol, ethanol, isopropanol or ethylacetate, a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulphoxide. The reaction is conveniently carried out at atemperature in the range, for example, 10 to 250° C., preferably in therange 40 to 120° C.

Typically, the quinazoline of the Formula II may be reacted with ananiline of the Formula III in the presence of a protic solvent such asisopropanol, conveniently in the presence of an acid, for examplehydrogen chloride gas in diethyl ether, and at a temperature in therange, for example, 25 to 150° C., preferably at or near the refluxtemperature of the reaction solvent.

The quinazoline derivative of the Formula I may be obtained from thisprocess in the form of the free base or alternatively it may be obtainedin the form of a salt with the acid of the formula H-L wherein L has themeaning defined hereinbefore. When it is desired to obtain the free basefrom the salt, the salt may be treated with a suitable base, forexample, an organic amine base such as, for example, pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or,for example, an alkali or alkaline earth metal carbonate or hydroxide,for example sodium carbonate, potassium carbonate, calcium carbonate,sodium hydroxide or potassium hydroxide.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(loweralkyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2-6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed cleavage.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkylgroups (for example benzyl and substituted benzyl, 4-methoxybenzyl,2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyland tert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such as2-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J.March, published by John Wiley & Sons 1992, for general guidance onreaction conditions and reagents and to Protective Groups in OrganicSynthesis, 2^(nd) Edition, by T. Green et al., also published by JohnWiley & Son, for general guidance on protecting groups.

Quinazoline starting materials of the Formula II may be obtained byconventional procedures. For example, a 3,4-dihydroquinazolin-4-one ofFormula IV

wherein m and R¹ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, may be reacted witha halogenating agent such as thionyl chloride, phosphoryl chloride or amixture of carbon tetrachloride and triphenylphosphine whereafter anyprotecting group that is present is removed by conventional means.

The 4-chloroquinazoline so obtained may be converted, if required, intoa 4-pentafluorophenoxyquinazoline by reaction with pentafluorophenol inthe presence of a suitable base such as potassium carbonate and in thepresence of a suitable solvent such as N,N-dimethylformamide.

7-Aminobenzofuran starting materials of the Formula III may be obtainedby conventional procedures as illustrated in the Examples.

-   (b) For the production of those compounds of the Formula I wherein    at least one R¹ group is a group of the formula    Q¹—X¹—-    wherein Q¹ is an aryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl,    (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl or    heterocyclyl-(1-6C)alkyl group or an optionally substituted alkyl    group and X¹ is an oxygen atom, the coupling, conveniently in the    presence of a suitable dehydrating agent, of a quinazoline of the    Formula V-    wherein m, R¹, R², n and R³ have any of the meanings defined    hereinbefore except that any functional group is protected if    necessary, with an appropriate alcohol wherein any functional group    is protected if necessary whereafter any protecting group that is    present is removed by conventional means.

A suitable dehydrating agent is, for example, a carbodiimide reagentsuch as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)3-ethylcarbodiimide or a mixture of an azocompound such as diethyl or di-tert-butyl azodicarboxylate and aphosphine such as triphenylphosphine. The reaction is convenientlycarried out in the presence of a suitable inert solvent or diluent, forexample a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride and at a temperature in the range, for example, 10to 150° C., preferably at or near ambient temperature.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride and at atemperature in the range, for example, 10 to 150° C., preferably at ornear ambient temperature.

-   (c) For the production of those compounds of the Formula I wherein    an R¹ group contains a primary or secondary amino group, the    cleavage of the corresponding compound of the Formula I wherein the    R¹ group contains a protected primary or secondary amino group.

Suitable protecting groups for an amino group are, for example, any ofthe protecting groups disclosed hereinbefore for an amino group.Suitable methods for the cleavage of such amino protecting groups arealso disclosed hereinbefore. In particular, a suitable protecting groupis a lower alkoxycarbonyl group such as a tert-butoxycarbonyl groupwhich may be cleaved under conventional reaction conditions such asunder acid-catalysed hydrolysis, for example in the presence oftrifluoroacetic acid.

-   (d) For the production of those compounds of the Formula I wherein    an R¹ group contains a (1-6C)alkoxy or substituted (1-6C)alkoxy    group or a (1-6C)alkylamino or substituted (1-6C)alkylamino group,    the alkylation, conveniently in the presence of a suitable base as    defined hereinbefore, of a quinazoline derivative of the formula I    wherein the R¹ group contains a hydroxy group or a primary or    secondary amino group as appropriate.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of amino to alkylamino or substituted alkylamino, forexample an alkyl or substituted alkyl halide, for example a (1-6C)alkylchloride, bromide or iodide or a substituted (1-6C)alkyl chloride,bromide or iodide, conveniently in the presence of a suitable base asdefined hereinbefore, in a suitable inert solvent or diluent as definedhereinbefore and at a temperature in the range, for example, 10 to 140°C., conveniently at or near ambient temperature.

Conveniently for the production of those compounds of the Formula Iwherein R¹ contains a (1-6C)alkylamino or substituted (1-6C)alkylaminogroup, a reductive amination reaction may be employed. For example, forthe production of those compounds of the Formula I wherein R¹ contains aN-methyl group, the corresponding compound containing a N—H group may bereacted with formaldehyde in the presence of a suitable reducing agent.A suitable reducing agent is, for example, a hydride reducing agent, forexample an alkali metal aluminium hydride such as lithium aluminiumhydride or, preferably, an alkali metal borohydride such as sodiumborohydride, sodium cyanoborohydride, sodium triethylborohydride, sodiumtrimethoxyborohydride and sodium triacetoxyborohydride. The reaction isconveniently performed in a suitable inert solvent or diluent, forexample tetrahydrofuran and diethyl ether for the more powerful reducingagents such as lithium aluminium hydride, and, for example, methylenechloride or a protic solvent such as methanol and ethanol for the lesspowerful reducing agents such as sodium triacetoxyborohydride and sodiumcyanoborohydride. The reaction is performed at a temperature in therange, for example, 10 to 80° C., conveniently at or near ambienttemperature.

-   (e) For the production of those compounds of the Formula I wherein    R¹ is an amino-hydroxy-disubstituted (1-6C)alkoxy group (such as    2-hydroxy-3-pyrrolidin-1-ylpropoxy or    3-[N-allyl-N-methylamino]-2-hydroxypropoxy), the reaction of a    compound of the Formula I wherein the R¹ group contains an    epoxy-substituted (1-6C)alkoxy group with a heterocyclyl compound or    an appropriate amine.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range 10 to 150° C., preferably at or near ambient temperature.

-   (f) For the production of those compounds of the Formula I wherein    an R¹ group contains a hydroxy group, the cleavage of the    corresponding compound of the Formula I wherein the R¹ group    contains a protected hydroxy group.

Suitable protecting groups for a hydroxy group are, for example, any ofthe protecting groups disclosed hereinbefore. Suitable methods for thecleavage of such hydroxy protecting groups are also disclosedhereinbefore. In particular, a suitable protecting group is a loweralkanoyl group such as an acetyl group which may be cleaved underconventional reaction conditions such as under base-catalysedconditions, for example in the presence of ammonia.

When a pharmaceutically-acceptable salt of a quinazoline derivative ofthe Formula I is required, for example an acid-addition salt, it may beobtained by, for example, reaction of said quinazoline derivative with asuitable acid using a conventional procedure.

Biological Assays

The following assays can be used to measure the effects of the compoundsof the present invention as c-Src tyrosine kinase inhibitors, asinhibitors in vitro of the proliferation of c-Src transfected fibroblastcells, as inhibitors in vitro of the migration of A549 human lung tumourcells and as inhibitors in vivo of the growth in nude mice of xenograftsof A549 tissue.

(a) In Vitro Enzyme Assay

The ability of test compounds to inhibit the phosphorylation of atyrosine containing polypeptide substrate by the enzyme c-Src kinase wasassessed using a conventional Elisa assay.

A substrate solution [100 μl of a 20 μg/ml solution of the polyaminoacid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphatebuffered saline (PBS) containing 0.2 mg/ml of sodium azide] was added toeach well of a number of Nunc 96-well immunoplates (Catalogue No.439454) and the plates were sealed and stored at 4° C. for 16 hours. Theexcess of substrate solution was discarded, and aliquots of Bovine SerumAlbumin (BSA; 150 μl of a 5% solution in PBS) were transferred into eachsubstrate-coated assay well and incubated for 1 hour at ambienttemperature to block non specific binding. The assay plate wells werewashed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and withHepes pH7.4 buffer (50 mM, 300 μl/well) before being blotted dry.

Each test compound was dissolved in dimethyl sulphoxide and diluted withdistilled water to give a series of dilutions (from 100 μM to 0.001 μM).Portions (25 μl) of each dilution of test compound were transferred towells in the washed assay plates. “Total” control wells containeddiluted DMSO instead of compound. Aliquots (25 μl) of an aqueousmagnesium chloride solution (80 mM) containing adenosine-5′-triphosphate(ATP; 40 μM) was added to all test wells except the “blank” controlwells which contained magnesium chloride without ATP.

Active human c-Src kinase (recombinant enzyme expressed in Sf9 insectcells; obtained from Upstate Biotechnology Inc. product 14-117) wasdiluted immediately prior to use by a factor of 1:10,000 with an enzymediluent which comprised 100 mM Hepes pH7.4 buffer, 0.2 mM sodiumorthovanadate, 2 mM dithiothreitol and 0.02% BSA. To start thereactions, aliquots (50 μl) of freshly diluted enzyme were added to eachwell and the plates were incubated at ambient temperature for 20minutes. The supernatant liquid in each well was discarded and the wellswere washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05-321; 100 μl) was diluted by afactor of 1:6000 with PBST containing 0.5% w/v BSA and added to eachwell. The plates were incubated for 1 hour at ambient temperature. Thesupernatant liquid was discarded and each well was washed with PBST(×4). Horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody(Amersham Catalogue No. NXA 931; 100 μl) was diluted by a factor of1:500 with PBST containing 0.5% w/v BSA and added to each well. Theplates were incubated for 1 hour at ambient temperature. The supernatantliquid was discarded and the wells were washed with PBST (×4).

A PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilledwater (100 ml) to provide phosphate-citrate pH5 buffer (50 mM)containing 0.03% sodium perborate. An aliquot (50 ml) of this buffer wasmixed with a 50 mg tablet of2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; BoehringerCatalogue No. 1204 521). Aliquots (100 μl) of the resultant solutionwere added to each well. The plates were incubated for 20 to 60 minutesat ambient temperature until the optical density value of the “total”control wells, measured at 405 nm using a plate readingspectrophotometer, was approximately 1.0. “Blank” (no ATP) and “total”(no compound) control values were used to determine the dilution rangeof test compound which gave 50% inhibition of enzyme activity.

(b) In Vitro c-Src Transfected NIH 3T3 (c-src 3T3) FibroblastProliferation Assay

This assay determined the ability of a test compound to inhibit theproliferation of National Institute of Health (NIH) mouse 3T3 fibroblastcells that had been stably-transfected with an activating mutant (Y530F)of human c-Src.

Using a similar procedure to that described by Shalloway et al., Cell,1987, 49, 65-73, NIH 3T3 cells were transfected with an activatingmutant (Y530F) of human c-Src. The resultant c-Src 3T3 cells weretypically seeded at 1.5×10⁴ cells per well into 96-welltissue-culture-treated clear assay plates (Costar) each containing anassay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma)plus 0.5% foetal calf serum (FCS), 2 mM glutamine, 100 units/mlpenicillin and 0.1 mg/ml streptomycin in 0.9% aqueous sodium chloridesolution. The plates were incubated overnight at 37° C. in a humidified(7.5% CO₂: 95% air) incubator.

Test compounds were solubilised in DMSO to form a 10 mM stock solution.Aliquots of the stock solution were diluted with the DMEM mediumdescribed above and added to appropriate wells. Serial dilutions weremade to give a range of test concentrations. Control wells to which testcompound was not added were included on each plate. The plates wereincubated overnight at 37° C. in a humidified (7.5% CO₂: 95% air)incubator.

BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) wasdiluted by a factor of 1:100 in DMEM medium containing 0.5% FCS andaliquots (20 μl) were added to each well to give a final concentrationof 10 μM). The plates were incubated at 37° C. for 2 hours. The mediumwas decanted. A denaturating solution (FixDenat solution, BoehringerMannheim Catalogue No. 647 229; 50 μl) was added to each well and theplates were placed on a plate shaker at ambient temperature for 45minutes. The supernatant was decanted and the wells were washed with PBS(200 μl per well). Anti-BrdU-Peroxidase solution (Boehringer MannheimCatalogue No. 647 229) was diluted by a factor of 1:100 in PBScontaining 1% BSA and 0.025% dried skimmed milk (Marvel (registeredtrade mark), Premier Beverages, Stafford, GB) and an aliquot (100 μl) ofthe resultant solution was added to each well. The plates were placed ona plate shaker at ambient temperature for 90 minutes. The wells werewashed with PBS (×5) to ensure removal of non bound antibody conjugate.The plates were blotted dry and tetramethylbenzidine substrate solution(Boehringer Mannheim Catalogue No. 647 229; 100 μl) was added to eachwell. The plates were gently agitated on a plate shaker while the colourdeveloped during a 10 to 20 minute period. The absorbance of the wellswas measured at 690 nm. The extent of inhibition of cellularproliferation at a range of concentrations of each test compound wasdetermined and an anti-proliferative IC₅₀ value was derived.

(c) In Vitro Microdroplet Migration Assay

This assay determines the ability of a test compound to inhibit themigration of adherent mammalian cell lines, for example the human tumourcell line A549.

RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose(Difco Catalogue No. 0142-01) was warmed to 37° C. in a water bath. Astock 2% aqueous agar solution was autoclaved and stored at 42° C. Analiquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml)immediately prior to its use. A549 cells (Accession No. ATCC CCL185)were suspended at a concentration of 2×10⁷ cells/ml in the medium andmaintained at a temperature of 37° C.

A droplet (2 μl ) of the cell/agarose mixture was transferred by pipetteinto the centre of each well of a number of 96-well, flat bottomednon-tissue-culture-treated microtitre plate (Bibby Sterilin CatalogueNo. 642000). The plates were placed briefly on ice to speed the gellingof the agarose-containing droplets. Aliquots (90 μl) of medium which hadbeen cooled to 4° C. were transferred into each well, taking care not todisturb the microdroplets. Test compounds were diluted from a 10 mMstock solution in DMSO using RPMI medium as described above. Aliquots(10 μl) of the diluted test compounds were transferred to the wells,again taking care not to disturb the microdroplets. The plates wereincubated at 37° C. in a humidified (7.5% CO₂:95% air) incubator forabout 48 hours.

Migration was assessed visually and the distance of migration wasmeasured back to the edge of the agar droplet. A migratory inhibitoryIC₅₀ was derived by plotting the mean migration measurement against testcompound concentration.

(d) In Vivo A549 Xenograft Growth Assay

This test measures the ability of compounds to inhibit the growth of theA549 human carcinoma grown as a tumour in athymic nude mice (AlderleyPark nu/nu strain). A total of about 5×10⁶ A549 cells in matrigel(Beckton Dickinson Catalogue No. 40234) were injected subcutaneouslyinto the left flank of each test mouse and the resultant tumours wereallowed to grow for about 14 days. Tumour size was measured twice weeklyusing callipers and a theoretical volume was calculated. Animals wereselected to provide control and treatment groups of approximately equalaverage tumour volume. Test compounds were prepared as a ball-milledsuspension in 1% polysorbate vehicle and dosed orally once daily for aperiod of about 28 days. The effect on tumour growth was assessed.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general activity possessedby compounds of the Formula I, may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a), (b), (c)and (d):

-   -   Test (a): IC₅₀ in the range, for example, 0.001-10 μM;    -   Test (b): IC₅₀ in the range, for example, 0.01-20 μM;    -   Test (c): activity in the range, for example, 0.01-25 μM;    -   Test (d): activity in the range, for example, 1-200 mg/kg/day.

No physiologically-unacceptable toxicity was observed in Test (d) at theeffective dose for compounds tested of the present invention.Accordingly no untoward toxicological effects are expected when acompound of Formula I, or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore is administered at the dosage ranges definedhereinafter.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinazoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.1 mg/kgto 30 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.05mg/kg to 25 mg/kg body weight will be used. Oral administration ishowever preferred, particularly in tablet form. Typically, unit dosageforms will contain about 0.5 mg to 0.5 g of a compound of thisinvention.

According to a further aspect of the invention there is provided aquinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore foruse in a method of treatment of the human or animal body by therapy.

As stated above, it is known that the predominant role of c-Srcnon-receptor tyrosine kinase is to regulate cell motility which isnecessarily required for a localised tumour to progress through thestages of dissemination into the blood stream, invasion of other tissuesand initiation of metastatic tumour growth. We have found that thequinazoline derivatives of the present invention possess potentanti-tumour activity which it is believed is obtained by way ofinhibition of one or more of the non-receptor tyrosine-specific proteinkinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells.

Accordingly the quinazoline derivatives of the present invention are ofvalue as anti-tumour agents, in particular as selective inhibitors ofthe motility, dissemination and invasiveness of mammalian cancer cellsleading to inhibition of metastatic tumour growth. Particularly, thequinazoline derivatives of the present invention are of value asanti-invasive agents in the containment and/or treatment of solid tumourdisease. Particularly, the compounds of the present invention areexpected to be useful in the prevention or treatment of those tumourswhich are sensitive to inhibition of one or more of the multiplenon-receptor tyrosine kinases such as c-Src kinase that are involved inthe signal transduction steps which lead to the invasiveness andmigratory ability of metastasising tumour cells. Further, the compoundsof the present invention are expected to be useful in the prevention ortreatment of those tumours which are mediated alone or in part byinhibition of the enzyme c-Src, i.e. the compounds may be used toproduce a c-Src enzyme inhibitory effect in a warm-blooded animal inneed of such treatment. Specifically, the compounds of the presentinvention are expected to be useful in the prevention or treatment ofsolid tumour disease.

Thus according to this aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use as an anti-invasive agent in thecontainment and/or treatment of solid tumour disease.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-invasive effect by thecontainment and/or treatment of solid tumour disease in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a quinazolinederivative of the Formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofsolid tumour disease in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of solid tumourdisease in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose tumours which are sensitive to inhibition of non-receptor tyrosinekinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours whichare sensitive to inhibition of non-receptor tyrosine kinases such asc-Src kinase that are involved in the signal transduction steps whichlead to the invasiveness and migratory ability of metastasising tumourcells which comprises administering to said animal an effective amountof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a c-Src kinaseinhibitory effect.

According to a further feature of this aspect of the invention there isprovided a method for providing a c-Src kinase inhibitory effect whichcomprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

The anti-invasive treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the quinazoline derivativeof the invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:

-   (i) other anti-invasion agents (for example metalloproteinase    inhibitors like marimastat and inhibitors of urokinase plasminogen    activator receptor function);-   (ii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as alkylating agents (for    example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea, or, for example, one of the preferred    antimetabolites disclosed in European Patent Application No. 562734    such as    (2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5yl)buturic    acid); antitumour antibiotics (for example anthracyclines like    adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,    idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic    agents (for example vinca alkaloids like vincristine, vinblastine,    vindesine and vinorelbine and taxoids like taxol and taxotere); and    topoisomerase inhibitors (for example epipodophyllotoxins like    etoposide and teniposide, amsacrine, topotecan and camptothecin);-   (iii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutaminde, nilutamnide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrazole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies, tyrosine kinase inhibitors and serine/threonine kinase    inhibitors, for example inhibitors of the epidermal growth factor    family (for example the EGFR tyrosine kinase inhibitors    N-(3-chloro-4-fluoropnenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4amine    (ZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (CP 358774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family; and-   (v) antiangiogenic agents such as those which inhibit vascular    endothelial growth factor such as the compounds disclosed in    International Patent Applications WO 97/22596, WO 97/30035, WO    97/32856 and WO 98/13354 and those that work by other mechanisms    (for example linomide, inhibitors of integrin αvβ3 function and    angiostatin).

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided apharmaceutical product comprising a quinazoline derivative of theformula I as defined hereinbefore and an additional anti-tumour agent asdefined hereinbefore for the conjoint treatment of cancer.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of c-Src.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following Examples inwhich, generally:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields, where present, are not necessarily the maximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a Jeo1JNM EX 400 spectrometer operating at a field strength of 400 MHz, VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM300 spectrometer operating at a field strength of 300 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture;

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide DMSO dimethylsulphoxide THF tetrahydrofuran

EXAMPLE 14-(7-benzofuranylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline

A mixture of4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (0.1g), 7-aminobenzofuran (0.057 g), isopropanol (4 ml) and a solution ofhydrogen chloride in isopropanol (6M, 0.06 ml) was stirred and heated to85° C. for 3 hours. The resultant mixture was cooled to ambienttemperature and the precipitate was isolated by filtration, washed inturn with a 1:1 mixture of diethyl ether and isopropanol and withdiethyl ether and dried under vacuum. There was thus obtained the titlecompound (0.09 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd₆ andCF₃COOD) 2.35 (m, 2H), 2.9 (s, 3H), 3.45 (br m, 5H), 3.8 (br m, 5H),4.05 (s, 3H), 4.35 (t, 2H), 7.1 (d, 1H), 7.45 (m, 3H), 7.75 (d, 1H),8.05 (s, 1H), 8.25 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H⁺ 448.

The 7-aminobenzofuran used as a starting material was prepared asfollows:

Hydrazine hydrate (0.45 ml) was added dropwise to a stirred mixture of7-nitrobenzofuran (J. Med. Chem., 1988, 31, 1934; 0.5 g), Raney nickel(0.02 g) and methanol (9 ml) that had been warmed to 55° C. Theresultant mixture was heated to reflux for 30 minutes. The catalyst wasremoved by filtration and the filtrate was evaporated. The residue waspartitioned between methylene chloride and water. The organic phase wasdried over magnesium sulphate and evaporated to give 7-aminobenzofuran(0.4 g) as an oil; NMR Spectrum: (DMSOd₆) 5.25 (br s, 2H), 6.55 (d, 1H),6.8 (m, 2H), 6.9 (t, 1H), 7.85 (d, 1H).

The 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolineused as a starting material was prepared as follows:

3-(4-Methylpiperazin-1-yl)propyl 4-toluenesulphonate was prepared asfollows:

A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml),potassium carbonate (83 g) and ethanol (200 ml)was stirred and heated toreflux for 20 hours. The mixture was cooled to ambient temperature andfiltered. The filtrate was evaporated and the residue was trituratedunder diethyl ether. The resultant mixture was filtered and the filtratewas evaporated. The residue was purified by distillation at about 60-70°C. under about 0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine(17 g); NMR Spectrum: (CDCl₃) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2.8 (m,8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H).

4-Toluenesulphonyl chloride (3.2 g) was added to a stirred mixture of1-(3-hydroxypropyl)-4-methylpiperazine (2.4 g), triethylamine (4.6 ml)and methylene chloride (60 ml) and the resultant mixture was stirred atambient temperature for 2 hours. The solution was washed in turn with asaturated aqueous sodium bicarbonate solution and with water andfiltered through phase separating paper. The organic filtrate wasevaporated to give 3-(4-methylpiperazin-1-yl)propyl 4-toluenesulphonateas an oil which crystallised on standing (3.7 g); Mass Spectrum: M+H⁺313.

The trifluoroacetic acid salt of4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was preparedas follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem.,1977, 20, 146-149; 10 g),(3-dimethylamino-2-azaprop-2-en-1-ylidene)dimethylammonium chloride(Gold's reagent, 7.4 g) and dioxane (100 ml) was stirred and heated toreflux for 24 hours. Sodium acetate (3.02 g) and acetic acid (1.65 ml)were added and the reaction mixture was heated for a further 3 hours.The mixture was evaporated and water was added to the residue. Theresultant solid was collected by filtration, washed with water anddried. The material was recrystallised from acetic acid to give7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g).

After repetition of the reaction so described, a mixture of7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-3,4-dihydroquinazolin-4-one(20.3 g), thionyl chloride (440 ml) and DMF (1.75 ml) was heated toreflux for 4 hours. The thionyl chloride was evaporated under vacuum andthe residue was azeotroped with toluene three times to give7-benzyloxy-4-chloro-6-methoxyquinazoline.

A mixture of the 7-benzyloxy-4-chloro-6-methoxyquinazoline so obtained,potassium carbonate (50 g) and 4-chloro-2-fluorophenol (8.8 ml) and DMF(500 ml) was stirred and heated to 100° C. for 5 hours. The mixture wasallowed to cool to ambient temperature, poured into water (2 L) andstirred at ambient temperature for a few minutes. The resultant solidwas isolated and washed with water. The solid was dissolved in methylenechloride and the solution was filtered and treated with decolourisingcharcoal. The resultant solution was filtered and evaporated to give asolid which was triturated under diethyl ether. There was thus obtained7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g);NMR Spectrum: (DMSOd₆) 3.98 (s, 3H), 5.34 (s, 2H), 7.42 (m, 9H), 7.69(m, 1H), 8.55 (s, 1H).

A mixture of the material so obtained and trifluoroacetic acid (15 ml)was heated to reflux for 3 hours. The reaction mixture was allowed tocool, toluene was added and the mixture was evaporated. The residue wastriturated under diethyl ether and then under acetone. The resultantprecipitate was isolated and dried to give4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazolinetrifluoroacetate salt (21.8 g) which was used without furtherpurification.

Thereafter, a mixture of the trifluoroacetic acid salt of4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g),3-(4-methylpiperazin-1-yl)propyl 4-toluenesulphonate (3.0 g), potassiumcarbonate (6.1 g) and DMF (60 ml) was stirred at 90° C. for 5 hours. Theresultant mixture was cooled to ambient temperature, poured into water(700 ml) and extracted with ethyl acetate (5 times). The combinedextracts were washed in turn with water, a saturated aqueous sodiumbicarbonate solution, water and brine. The ethyl acetate solution wasdried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography on silica using a 100:8:1 mixture of methylenechloride, methanol and a concentrated aqueous ammonium hydroxidesolution (0.880 g/ml) as eluent. The material so obtained was trituratedunder diethyl ether. There was thus obtained4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline(1.64 g); NMR Spectrum: (DMSOd₆) 1.95 (m, 2H), 2.14 (s, 3H), 2.35 (m,8H), 2.44 (t, 2H), 3.96 (s, 3H), 4.22 (t, 2H), 7.38 (s, 1H), 7.4 (m,1H), 7.54 (m, 2H), 7.68 (m, 1H), 8.5 (s, 1H).

After repetition of the previous reaction, a mixture of4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-[3-(4-methylpiperazine-1-yl)propozy]quinazoline(2.6 g) and 2N aqueous hydrochloric acid solution (45 ml) was stirredand heated to 95° C. for 2 hours. The mixture was cooled to ambienttemperature and basified by the addition of solid sodium bicarbonate Themixture was evaporated and the residue was purified by columnchromatography on silica using a 50:8:1 mixture of methylene chloride,methanol and a concentrated aqueous ammonium hydroxide solution (0.880g/ml) as eluent. There was thus obtained6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-3,4-dihydroquinazolin-4-one(1.8 g,); Mass Spectrum: M+H⁺ 333.

After repetition of the previous reaction, a mixture of6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-3,4-dihydroquinazoline-4-one(2.15 g), thionyl chloride (25 ml) and DMF (0.18 ml) was stirred andheated to reflux for 2 hours. The thionyl chloride was evaporated undervacuum and the residue azeotroped twice with toluene. The residue wastaken up in water, basified by the addition of a saturated aqueoussodium bicarbonate solution and extracted with methylene chloride (4times). The combined extracts were washed in turn with water and brineand filtered through phase separating paper. The filtrate was evaporatedunder vacuum and the residue was purified by column chromatography onsilica using a 100:8:1 mixture of methylene chloride, methanol and aconcentrated aqueous ammonium hydroxide solution (0.880 g/ml) as eluent.The solid so obtained was triturated under acetone, filtered and driedto give4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (1.2g); Mass Spectrum: M+H⁺ 351.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate 4-chloroquinazoline was reacted with the appropriate7-aminobenzofuran to give the compounds described in Table I. Unlessotherwise stated, each compound described in Table I was obtained as adihydrochloride salt.

TABLE I

No. R¹ R² Note 1 3-morpholinopropoxy hydrogen [1] 2 3-morpholinopropoxy5-methoxy [2] 3 3-(4-methylpiperazin-1-yl)propoxy 5-methoxy [3] 43-morpholinopropoxy 3-chloro [4] 5 3-(4-methylpiperazin-1-yl)propoxy3-chloro [5] 6 3-morpholinopropoxy 5-fluoro [6] 73-(4-methylpiperazin-1-yl)propoxy 5-fluoro [7] 82-acetoxy-3-morpholinopropoxy 3-chloro [8] 92-acetoxy-3-(N-isopropyl-N-methylamino)- 3-chloro [9] propoxy 102-acetoxy-3-(4-cyanomethylpiperazin-1-yl)- 3-chloro [10] propoxy 112-acetoxy-3-pyrrolidin-1-ylpropoxy 3-chloro [11] 122-acetoxy-3-piperidinopropoxy 3-chloro [12] Notes [1] The product gavethe following characterising data; NMR Spectrum: (DMSOd₆ and CF₃COOD)2.35 (m, 2H), 3.15 (t, 2H), 3.35 (t, 2H), 3.55 (d, 2H), 3.75 (t, 2H),4.05 (t, 3H), 4.1 (m, 2H), 4.35 (t, 2H), 7.1 (d, 1H), 7.45 (m, 3H), 7.75(d, 1H), 8.05 (d, 1H), 8.25 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M + H⁺435.

The 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline used as astarting material was prepared as follows:

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (35 g),thionyl chloride (440 ml) and DMF (1.75 ml) was heated to reflux for 4hours. The thionyl chloride was evaporated under vacuum and the residuewas azeotroped with toluene three times. The residue was dissolved inN-methylpyrrolidin-2-one (250 ml) to give a solution of7-benzyloxy-4-chloro-6-methoxyquinazoline.

Phenol (29.05 g) was dissolved in N-methylpyrrolidin-2-one (210 ml) andsodium hydride (60% dispersion in mineral oil; 11.025 g) was added inportions with cooling. The resultant mixture was stirred at ambienttemperature for 3 hours. The resultant viscous suspension was dilutedwith N-methylpyrrolidin-2-one (180 ml) and stirred overnight. Theabove-mentioned solution of 7-benzyloxy-4-chloro-6-methoxyquinazolinewas added and the resultant suspension was stirred and heated to 100° C.for 2.5 hours. The mixture was allowed to cool to ambient temperatureand poured into water (1.5 L) with vigorous stirring. The precipitatewas collected by filtration, washed with water and dried under vacuum.The material so obtained was dissolved in methylene chloride and thesolution was washed with brine and filtered through phase separatingpaper. The solution was evaporated under vacuum and the resultantresidue was triturated under diethyl ether. There was thus obtained7-benzyloxy-6-methoxy-4-phenoxyquinazoline (87.8 g); NMR Spectrum:(CDCl₃) 4.09 (s, 3H), 5.34 (s, 2H), 7.42 (m, 12H), 7.63 (s, 1H).

A mixture of a portion (36.95 g) of the material so obtained andtrifluoroacetic acid (420 ml) was heated to reflux for 3 hours. Thereaction mixture was allowed to cool and evaporated under vacuum. Theresidue was stirred mechanically under water, basified by the additionof a saturated aqueous sodium bicarbonate solution and stirredovernight. The water was decanted and the residual solid was suspendedin acetone. After stirring, the white solid was collected by filtration,washed with acetone and dried to give7-hydroxy-6-methoxy-4-phenoxyquinazoline (26.61 g); NMR Spectrum:(DMSOd₆) 3.97 (s, 3H), 7.22 (s, 1H), 7.3 (m, 3H), 7.47 (t, 2H), 7.56 (s,1H), 8.47 (s, 1H), 10.7 (s, 1H).

A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (25.27 g),3-morpholinopropyl chloride (18.48 g), potassium carbonate (39.1 g) andDMF (750 ml) was stirred and heated to 90° C. for 3 hours. The mixturewas allowed to cool to ambient temperature and filtered. The filtratewas evaporated and the residue was triturated under ethyl acetate. Therewas thus obtained 6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline(31.4 g); NMR Spectrum: (DMSOd₆) 1.97 (m, 2H), 2.39 (t, 4H), 2.47 (t,2H), 3.58 (t, 4H), 3.95 (s, 3H), 4.23 (t, 2H), 7.31 (m, 3H), 7.36 (s,1H), 7.49 (t, 2H), 7.55 (s, 1H), 8.52 (s, 1H).

A mixture of the material so obtained and 6N aqueous hydrochloric acidsolution (800 ml) was stirred and heated to reflux for 1.5 hours. Thereaction mixture was decanted and concentrated to a volume of 250 ml.The mixture was basified to pH9 by the addition of a saturated aqueoussodium bicarbonate solution and extracted with methylene chloride (4×400ml). The combined extracts were filtered through phase separating paperand the filtrate was evaporated. The resultant solid was trituratedunder ethyl acetate to give6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g);NMR Spectrum: (DMSOd₆) 1.91 (m, 2H), 2.34 (t, 4H), 2.42 (t, 2H), 3.56(t, 4H), 3.85 (s, 3H), 4.12 (t, 2H), 7.11 (s, 1H), 7.42 (s, 1H), 7.96(s, 1H), 12.01 (s, 1H).

A mixture of the material so obtained, thionyl chloride (210 ml) and DMF(1.8 ml) was heated to reflux for 1.5 hours. The thionyl chloride wasremoved by evaporation under vacuum and the residue was azeotroped withtoluene three times. The residue was taken up in water and basified topH8 by the addition of a saturated aqueous sodium bicarbonate solution.The resultant aqueous layer was extracted with methylene chloride (4×400ml). The combined extracts were washed with water and with brine anddried over magnesium sulphate. The solution was filtered and evaporated.The resultant solid was triturated under ethyl acetate to give4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (17.39 g); NMRSpectrum: (CDCl₃) 2.1-2.16 (m, 2H), 2.48 (br s, 4H), 2.57 (t, 2H), 3.73(t, 4H), 4.05 (s, 3H), 4.29 (t, 2H), 7.36 (s, 1H), 7.39 (s, 1H), 8.86(s, 1H).

The 3-morpholinopropyl chloride used as a reagent was obtained asfollows:

A mixture of morpholine (52.2 ml), 1-bromo-3-chloropropane (30 ml) andtoluene (180 ml) was heated to 70° C. for 3 hours. The solid was removedby filtration and the filtrate was evaporated under vacuum. Theresultant oil was decanted from the additional solid which was depositedand the oil was purified by vacuum distillation to yield3-morpholinopropyl chloride (37.91 g); NMR Spectrum: (DMSOd₆) 1.85 (m,2H), 2.3 (t, 4H), 2.38 (t, 2H), 3.53 (t, 4H), 3.65 (t, 2H).

-   [2] Pentan-2-ol was used in place of isopropanol as the reaction    solvent and the reaction mixture was heated to 85° C. for 1 hour.    The product gave the following characterising data; NMR Spectrum:    (DMSOd₆ and CF₃COOD) 2.35 (m, 2H), 3.15 (m, 2H), 3.35 (t, 2H), 3.55    (d, 2H), 3.75 (t, 2H), 3.85 (s, 3H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35    (t, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.25 (d, 1H), 7.4 (s, 1H), 8.0    (d, 1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 465.

The 7-amino-5-methoxybenzofuran used as a starting material was preparedas follows:

2-Hydroxy-5-methoxybenzaldehyde was reacted with ceric ammonium nitrateaccording to the procedure described in Synth. Comm., 1999, 1201 to give2-hydroxy-5-methoxy-3-nitro-benzaldehyde.

A mixture of 2-hydroxy-5-methoxy-3-nitrobenzaldehyde (1 g), diethylbromomalonate (0.95 ml), potassium carbonate (1.05 g),tetrabutylammonium bromide (0.163 g) and toluene (20 ml) was stirred andheated to reflux in a Dean & Stark apparatus for 20 hours. The mixturewas cooled to ambient temperature, filtered and the filtrate wasevaporated. The residue was dissolved in methylene chloride and thesolution was washed in turn with water, with a 1N aqueous potassiumhydroxide solution and with brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 4:1 mixture of methylene chloride and petroleum ether (b.p.60-80° C.) as eluent. There was thus obtained ethyl5-methoxy-7-nitrobenzofuran-2-carboxylate (0.264 g); NMR Spectrum:(DMSOd₆) 1.35 (t, 3H), 3.9 (s, 3H), 4.4 (q, 2H), 7.8 (d, 1H), 7.85 (s,1H), 7.9 (d, 1H).

After repetition of the preceding reaction, a mixture of ethyl5-methoxy-7-nitrobenzofuran-2-carboxylate (0.5 g), 2N aqueous potassiumhydroxide solution (1.8 ml) and ethanol (20 ml) was stirred and heatedto reflux for 1 hour. The ethanol was evaporated and the residue wasdissolved in water. The solution was acidified to pH1 by the addition of6N aqueous hydrochloric acid. The resultant precipitate was isolated,washed with water and dried under vacuum over phosphorus pentoxide togive 5-methoxy-7-nitrobenzofuran-2-carboxylic acid (0.33 g); NMRSpectrum: (DMSOd₆) 3.95 (s, 3H), 7.8 (s, 1H), 7.85 (d, 1H), 7.9 (d, 1H).

A mixture of the material so obtained, cupric (II) oxide (0.016 g),copper powder (0.015 g) and quinoline (3 ml) was heated to 220° C. for30 minutes. The mixture was cooled to ambient temperature and filtered.The filtrate was partitioned between diethyl ether and 2N aqueoushydrochloric acid. The organic phase was dried over magnesium sulphateand evaporated. The residue was purified by column chromatography onsilica using a 3:2 mixture of petroleum ether (b.p. 60-80° C.) and ethylacetate as eluent. There was thus obtained 5-methoxy-7-nitrobenzofuran(0.25 g); NMR Spectrum: (DMSOd₆), 3.9 (s, 3H), 7.15 (d, 1H), 7.7 (d,1H), 7.75 (d, 1H), 8.25 (d, 1H).

Hydrazine hydrate (0.188 ml) was added dropwise to a stirred mixture of5-methoxy-7-nitrobenzofuran (0.25 g), Raney nickel (0.02 g) and methanol(10 ml) that had been warmed to 55-60° C. The reaction mixture was thenheated to reflux for 45 minutes. The catalyst was removed by filtrationand the filtrate was evaporated. The residue was partitioned betweenmethylene chloride and water. The organic phase was dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 3:2 mixture of petroleum ether (b.p.60-80° C.) and ethyl acetate as eluent. There was thus obtained7-amino-5-methoxybenzofuran (0.153 g); NMR Spectrum: (DMSOd₆) 3.7 (s,3H), 5,3 (s, 2H), 6.2 (d, 1H), 6.35 (d, 1H), 6.75 (d, 1H), 7.85 (d, 1H).

-   [3] Pentan-2-ol was used in place of isopropanol as the reaction    solvent and the reaction mixture was heated to 120° C. for 4 hours.    The product gave the following characterising data; NMR Spectrum:    (DMSOd₆ and CF₃COOD) 2.35 (m, 2H), 2.95 (s, 3H), 3.4 (br s, 5H), 3.8    (br s, 5H), 3.85 (s, 3H), 4.05 (s, 3H), 4.35 (t, 2H), 7.0 (d, 1H),    7.10 (d, 1H), 7.25 (d, 1H), 7.4 (s, 1H), 8.0 (d, 1H), 8.25 (s, 1H),    8.85 (s, 1H); Mass Spectrum: M+H⁺ 478.-   [4] The product gave the following characterising data; NMR    Spectrum: (DMSOd₆ and CF₃COOD) 2.3 (m, 2H), 3.15 (t, 2H), 3.35 (t,    2H), 3.55 (d, 2H), 3.75 (t, 2H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35 (t,    2H), 7.3 (s, 1H), 7.55 (t, 1H), 7.6 (d, 1H), 7.7 (d, 1H), 8.2 (s,    1H), 8.4 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 469.

The 7-amino-3-chlorobenzofuran used as a starting material was preparedas follows:

7-Nitrobenzofuran (1.2 g) was dissolved in glacial acetic acid (12 ml)and chlorine gas was bubbled through the solution for 30 minutes whilstthe temperature of the reaction mixture was maintained at about 18° C.The reaction mixture was evaporated and the residue was purified bycolumn chromatography using a 1:1 mixture of petroleum ether (b.p.60-80° C.) and ethyl acetate as eluent. There was thus obtained amixture of the cis- and trans-isomers of2,3-dichloro-7-nitro-2,3-dihydrobenzofuran (0.77 g); Mass Spectrum: M+H⁺233.

After repetition of the preceding reaction, cis- andtrans-2,3-dichloro-7-nitro-2,3-dihydrobenzofuran (0.85 g) was dissolvedin ethanol (35 ml) and a 0.8N aqueous potassium hydroxide solution (45.5ml) was added. The reaction mixture was stirred at ambient temperaturefor 1.25 hours. The mixture was concentrated by evaporation, water wasadded and the mixture was acidified to pH2 by the addition of 6N aqueoushydrochloric acid. The mixture was extracted with diethyl ether. Theorganic phase was washed with water and with brine, dried over magnesiumsulphate and evaporated. There was thus obtained3-chloro-7-nitrobenzofuran (0.7 g) as a colorless solid; NMR Spectrum:(DMSOd₆) 7.65 (t, 1H), 8.15 (d, 1H), 8.3 (d, 1H), 8.65 (s, 1H).

The material so obtained was dissolved in methanol (25 ml) was thesolution was added dropwise during 5 minutes to a stirred mixture ofhydrazine hydrate (0.81 ml), Raney nickel (0.16 g) and methanol (30 ml)which had been heated to 60° C. The resultant reaction mixture was thenheated to reflux for 5 minutes. The reaction mixture was cooled toambient temperature and the catalyst was removed by filtration. Thefiltrate was evaporated and the residue was partitioned betweenmethylene chloride and water. The organic phase was dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 1:1 mixture of petroleum ether (b.p.60-80° C.) and ethyl acetate as eluent. There was thus obtained7-amino-3-chlorobenzofuran (0.41 g); NMR Spectrum: (DMSOd₆) 5.5 (br s,2H), 6.65 (d, 1H), 6.75 (d, 1H), 7.05 (t, 1H), 8.2 (s, 1H).

-   [5] Pentan-2-ol was used in place of isopropanol as the reaction    solvent and the reaction mixture was heated to 110° C. for 5 hours.    The product gave the following characterising data; NMR Spectrum:    (DMSOd₆ and CF₃COOD) 2.35 (m, 2H), 2.95 (s, 3H), 3.4 (br s, 5H), 3.8    (br s, 5H), 4.05 (s, 3H), 4.35 (m, 2H), 7.4 (s, 1H), 7.55 (t, 1H),    7.6 (d, 1H), 7.7 (d, 1H), 8.25 (s, 1H), 8.4 (s, 1H), 8.85 (s, 1H);    Mass Spectrum: M+H⁺ 482.-   [6] Pentan-2-ol was used in place of isopropanol as the reaction    solvent and the reaction mixture was heated to 85° C. for 1 hour.    The product gave the following characterising data; NMR Spectrum:    (DMSOd₆ and CF₃COOD) 2.35 (m, 2H), 3.15 (m, 2H), 3.35 (t, 2H), 3.55    (d, 2H), 3.75 (t, 2H), 4.0 (m, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.1    (d, 1H), 7.4 (m, 2H), 7.6 (m, 1H), 8.1 (d, 1H), 8.25 (s, 1H), 8.9    (s, 1H); Mass Spectrum: M+H⁺ 453.

The 7-amino-5-fluorobenzofuran used as a starting material was preparedas follows:

Allyl bromide (6 ml) was added to a stirred mixture of3-fluoro-2-nitrophenol (10 g), 1,5,7-triazabicyclo[4,4,0]dec-5-ene (11.5g) and DMF (120 ml) and the reaction mixture was stirred at ambienttemperature for 20 hours. The reaction mixture was then heated to 50° C.for 1.5 hours. The mixture was evaporated and the residue waspartitioned between diethyl ether and water. The organic phase waswashed in turn with a 1N aqueous hydrochloric acid solution, water andbrine, dried over magnesium sulphate and evaporated. There was thusobtained 4-allyloxy-3-nitro-1-fluorobenzene (9.6 g); NMR Spectrum:(DMSOd₆) 4.85 (d, 2H), 5.3 (d, 1H), 5.45 (d, 1H), 6.05 (m, 1H), 7.4 (m,1H), 7.6 (m, 1H), 7.9 (m, 1H).

A mixture of 4-allyloxy-3-nitro-1-fluorobenzene (8 g) and1,2-dichlorobenzene (14 ml) was heated to 230° C. for 32 minutes in amicrowave oven (651 W for 3 minutes to raise the temperature to 230° C.and then 300 W for 29 min). The solvent was evaporated and the residuewas mixed with methylene chloride (30 ml) and filtered. The filtrate wasevaporated and the residue was purified by column chromatography onsilica using a 4:1 mixture of petroleum ether (b.p. 60-80° C.) andmethylene chloride as eluent. There was thus obtained2-allyl-4-fluoro-6-nitrophenol (3.5 g) as an oil; NMR Spectrum: (DMSOd₆)3.45 (d, 2H), 5.1 (d, 2H); 6.0 (m, 1H), 7.5 (m, 1H), 7.75 (m, 1H), 0.4(br s, 1H).

The material so obtained was dissolved in methanol and cooled to −78° C.Ozone was bubbled through the solution for 30 minutes. Dimethyl sulfide(5.4 ml) was added and the reaction mixture was allowed to warm toambient temperature. The mixture was evaporated and the residue waspartitioned between diethyl ether and water. The organic phase waswashed in turn with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and methylenechloride and then a 9:1 mixture of methylene chloride and diethyl etheras eluent. There was thus obtained2-(5-fluoro-2-hydroxy-3-nitrophenyl)acetaldehyde which was immediatelysuspended in 85% phosphoric acid (18 ml) and the mixture was heated to100° C. for 1 hour. The mixture was cooled to ambient temperature andpartitioned between diethyl ether and water. The organic phase waswashed in turn with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and methylenechloride as eluent. There was thus obtained 5-fluoro-7-nitrobenzofuran(1.3 g); NMR Spectrum: (DMSOd₆) 7.2 (d, 1H), 8.05 (m, 2H), 8.35 (d, 1H).

Hydrazine hydrate (0.522 ml) was added dropwise to a stirred mixture of5-fluoro-7-nitrobenzofuran (0.65 g), Raney nickel (0.03 g) and methanol(12 ml) that had been warmed to 55-60° C. The reaction mixture was thenheated to reflux for 45 minutes. The catalyst was removed by filtrationand the filtrate was evaporated. The residue was partitioned betweenmethylene chloride and water. The organic phase was dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using increasingly polar mixtures of petroleumether (b.p. 60-80° C.) and methylene chloride as eluent. There was thusobtained 7-amino-5-fluorobenzofuran (0.206 g); NMR Spectrum: (DMSOd₆)5.65 (br s, 2H), 6.3 (m, 1H), 6.55 (m, 1H), 6.8 (d, 1H), 7.9 (d, 1H).

-   [7] Pentan-2-ol was used in place of isopropanol as the reaction    solvent and the reaction mixture was heated to 115° C. for 5 hours.    The product gave the following characterising data; NMR Spectrum:    (DMSOd₆ and CF₃COOD) 2.35 (m, 2H), 2.9 (s, 3H), 3.4 (br s, 5H), 3.8    (br s, 5H), 4.05 (s, 3H), 4.35 (t, 2H), 7.1 (d, 1H), 7.4 (m, 2H),    7.55 (m, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.85 (s, 1H); Mass Spectrum:    M+H⁺ 466.-   [8] The product gave the following characterising data; Mass    Spectrum: M+H⁺ 527 and 529.

The 7-(2-acetoxy-3-morpholinopropoxy)-4-chloro-6-methoxyquinazoline usedas a starting material was prepared as follows:

Sodium hydride (60% suspension in mineral oil, 1.44 g) was addedportionwise during 20 minutes to a solution of7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (International PatentApplication WO 97/22596, Example 1 thereof; 8.46 g) in DMF (70 ml). Themixture was stirred at ambient temperature for 1.5 hours. Chloromethylpivalate (5.65 g) was added dropwise and the mixture was stirred atambient temperature for 2 hours. The mixture was diluted with ethylacetate (100 ml) and poured onto a mixture (400 ml) of ice and watercontaining 2N aqueous hydrochloric acid (4 ml). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over magnesium sulphateand evaporated. The residue was triturated under a mixture of diethylether and petroleum ether (b.p. 60-80° C.) and the resultant solid wascollected and dried under vacuum. There was thus obtained7-benzyloxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazol (10 g);NMR Spectrum: (DMSOd₆) 1.11 (s, 9H), 3.89 (s, 3H), 5.3 (s, 2H), 5.9 (s,2H), 7.27 (s, 1H), 7.35 (m, 1H), 7.47 (t, 2H), 7.49 (d, 2H), 7.51 (s,1H), 8.34 (s, 1H).

A mixture of a portion (7 g) of the material so obtained, 10%palladium-on-charcoal catalyst (0.7 g), DMF (50 ml), methanol (50 ml),acetic acid (0.7 ml) and ethyl acetate (250 ml) was stirred under anatmosphere pressure of hydrogen for 40 minutes. The catalyst was removedby filtration and the solvent was evaporated. The residue was trituratedunder diethyl ether and the resultant solid was collected and driedunder vacuum. There was thus obtained7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(4.36 g); NMR Spectrum: (DMSOd₆) 1.1 (s, 9H), 3.89 (s, 3H), 5.89 (s,2H), 7.0 (s, 1H), 7.48 (s, 1H), 8.5 (s, 1H).

A mixture of7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (40g), 2,3-epoxypropyl bromide (16.8 ml), potassium carbonate (36 g) andDMF (400 ml) was stirred and heated to 70° C. for 1.5 hours. The mixturewas poured into an ice-water mixture (1.5 L) and the resultantprecipitate was isolated, washed in turn with water and diethyl etherand dried under vacuum over phosphorus pentoxide. There was thusobtained7-(2,3-epoxypropoxy)-6-methoxy-3-pivaloyloxy(ethyl-3,4-dihydroquinazolin-4-one(46.7 g).

A mixture of a portion (8 g) of the material so obtained, morpholine(5.8 ml) and chloroform (120 ml) was heated to reflux for 16 hours. Themixture was evaporated and the residue was purified by columnchromatography on silica using a 19:1 mixture of methylene chloride andmethanol as eluent. There was thus obtained7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-oneas a foam (8.2 g); NMR Spectrum: (CDCl₃) 1.2 (s, 9H), 2.5 (m, 2H), 2.6(m, 2H), 2.7 (m, 2H), 3.5 (br s, 1H), 3.75 (m, 4H), 3.95 (s, 3H), 4.15(m, 2H), 4.25 (m, 1H), 5.95 (s, 2H), 7.15 (s, 1H), 7.65 (s, 1H), 8.2 (s,1H).

A mixture of the material so obtained and a saturated methanolic ammoniasolution was stirred at ambient temperature for 24 hours. The mixturewas evaporated and the resultant solid was washed with diethyl ether anda 19:1 mixture of diethyl ether and methylene chloride. There was thusobtained7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(6.34 g); NMR Spectrum: (DMSOd₆) 2.4 (m, 6H), 3.55 (m, 4H), 3.85 (s,3H), 4.0 (m, 2H), 4.15 (m, 1H), 4.95 (br s, 1H), 7.15 (s, 1H), 7.45 (s,1H), 7.95 (s, 1H).

A mixture of a portion (5.2 g) of the material so obtained, aceticanhydride (20 ml) and pyridine (1 ml) was stirred at ambient temperaturefor 30 minutes. The resultant mixture was poured into an ice-watermixture and stirred for 30 minutes. The mixture was then cooled in anice-bath and a saturated solution of sodium bicarbonate was slowly addedto adjust the pH to 9. The mixture was extracted with methylene chlorideand the organic phase was washed with water and with brine, dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using a 93:7 mixture of methylene chloride andmethanol as eluent. There was thus obtained7-(2-acetoxy-3-morpholinopropoxy)-6-methoxy-3,4-dihydroquinazolin-4-oneas a solid (5 g); NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.4 (m, 4H), 2.6(m, 2H), 3.55 (m, 4H), 3.85 (s, 3H), 4.35 (m, 2H), 5.25 (m, 1H), 7.2 (s,1H), 7.45 (s, 1H), 8.0 (s, 1H); Mass Spectrum: M+H⁺ 378.

A mixture of the material so obtained, thionyl chloride (60 ml) and DMF(0.5 ml) was heated to reflux for 1 hour. The mixture was evaporated,toluene was added and the mixture was evaporated. A mixture of ice andwater was added to the residue and the mixture was basified to pH8.5 bythe addition of a saturated aqueous sodium bicarbonate solution. Themixture was extracted with methylene chloride. The organic phase waswashed with water and with brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 97:3 mixture of methylene chloride and methanol as eluent. Therewas thus obtained7-(2-acetoxy-3-morpholinopropoxy)-4-chloro-6-methoxyquinazoline as afoam (4.56 g); NMR Spectrum: (CDCl₃) 2.1 (s, 3H), 2.55 (m, 4H), 2.7 (d,2H), 3.7 (m, 4H), 4.05 (s, 3H), 4.35 (m, 1H), 4.45 (m, 1H), 5.45 (m,1H), 7.4 (d, 2H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 396 and 398.

-   [9] The product gave the following characterising data; Mass    Spectrum: M+H⁺ 513.

The7-[2-acetoxy-3-(N-isopropyl-N-methylamino)propoxy]-4-chloro-6-methoxyquinazolineused as a starting material was prepared as follows:

7-(2,3-Epoxypropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-onewas reacted with N-isopropyl-N-methylamine using an analogous procedureto that described in the fourth paragraph of the portion of Note [8]immediately above that is concerned with the preparation of startingmaterials. There was thus obtained7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one.

The material so obtained was taken through an analogous sequence ofreactions to those described in the fifth to seventh paragraphs of theportion of Note [8] immediately above that is concerned with thepreparation of starting materials. There was thus obtained7-[2-acetoxy-3-(N-isopropyl-N-methylamino)propoxy]-4-chloro-6-methoxyquinazoline;NMR Spectrum: (CDCl₃) 1.0 (d, 6H), 2.1 (s, 3H), 2.3 (s, 3H), 2.6 (m,1H), 2.75 (m, 1H), 2.85 (m, 1H), 4.05 (s, 3H), 4.35 (m, 1H), 4.45 (m,1H), 5.35 (m, 1H), 7.25 (s, 1H), 7.4 (s, 1H), 8.85 (s, 1H).

-   [10] The product gave the following characterising data; Mass    Spectrum: M+H⁺ 565.

The7-[2-acetoxy-3-(4-cyanomethylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazolineused as a starting material was prepared as follows:

7-(2,3-Epoxypropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-onewas reacted with 1-cyanomethylpiperazine using an analogous procedure tothat described in the fourth paragraph of the portion of Note [8]immediately above that is concerned with the preparation of startingmaterials. There was thus obtained7-[3-(4-cyanomethylpiperazin-1-yl)-2-hydroxypropoxy]-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one.

The material so obtained was taken through an analogous sequence ofreactions to those described in the fifth to seventh paragraphs of theportion of Note [8] immediately above that is concerned with thepreparation of starting materials. There was thus obtained7-[2-acetoxy-3-(4-cyanomethylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline;NMR Spectrum: (CDCl₃) 2.1 (s, 3H), 2.65 (br s, 10H), 3.5 (s, 2H), 4.05(s, 3H), 4.4 (m, 2H), 5.45 (m, 1H), 7.25 (s, 1H), 7.4 (s, 1H), 8.85 (s,1H); Mass Spectrum: M+H⁺ 434 and 436.

The 1-cyanomethylpiperazine used as a starting material was prepared asfollows:

A mixture of 1-(tert-butoxycarbonyl)piperazine (5 g),2-chloroacetonitrile (1.9 ml), potassium carbonate (4 g) and DMF (20 ml)was stirred at ambient temperature for 16 hours. A saturated aqueousammonium chloride solution was added and the mixture was extracted withethyl acetate. The organic phase was dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing diethyl ether as eluent. There was thus obtained1-(tert-butoxycarbonyl)-4-cyanomethylpiperazine as a solid (5.7 g); NMRSpectrum: (CDCl₃) 1.45 (s, 9H), 2.5 (m, 4H), 3.45 (m, 4H), 3.55 (s, 2H).

A mixture of the material so obtained, trifluoroacetic acid (20 ml) andmethylene chloride (25 ml) was stirred at ambient temperature for 4hours. The mixture was evaporated, toluene was added and the mixture wasevaporated again. The residue was purified by column chromatography onsilica using a 9:1 mixture of methylene chloride and methanol as eluent.There was thus obtained 1-cyanomethylpiperazine trifluoroacetate saltwhich was treated with solid sodium bicarbonate in a mixture ofmethylene chloride, ethyl acetate and methanol to give the free baseform (2.9 g); NMR Spectrum: (CDCl₃ and DMSOd₆) 2.7 (m, 4H), 3.2 (m, 4H),3.6 (s, 2H), 6.2 (br s, 1H).

-   [11] The product gave the following characterising data; Mass    Spectrum M+H⁺ 511.

The 7-(2-acetoxy-3-pyrrolidin-1-ylpropoxy)-4-chloro-6-methoxyquinazolineused as a starting material was prepared as follows:

7-(2,3-Epoxypropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-onewas reacted with pyrrolidine using an analogous procedure to thatdescribed in the fourth paragraph of the portion of Note [8] immediatelyabove that is concerned with the preparation of starting materials.There was thus obtained7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one.

The material so obtained was taken through an analogous sequence ofreactions to those described in the fifth to seventh paragraphs of theportion of Note [8] immediately above that is concerned with thepreparation of starting materials. There was thus obtained7-(2-acetoxy-3-pyrrolidin-1-ylpropoxy)-4-chloro-6-methoxyquinazoline;NMR Spectrum: (CDCl₃ and CD₃CO₂D) 2.05 (s, 4H), 2.15 (s, 3H), 3.45 (brs, 4H), 3.65 (m, 2H), 4.05 (s, 3H), 4.4 (d, 2H), 5.65 (m, 1H), 7.4 (s,1H), 7.55 (s, 1H), 8.9 (s, 1H).

-   [12] The product gave the following characterising data; Mass    Spectrum M+H⁺ 525.

The 7-(2-acetoxy-3-piperidinopropoxy)-4-chloro-6-methoxyquinazoline usedas a starting material was prepared as follows:

7-(2,3-Epoxypropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-onewas reacted with piperidine using an analogous procedure to thatdescribed in the fourth paragraph of the portion of Note [8] immediatelyabove that is concerned with the preparation of starting materials.There was thus obtained7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one.

The material so obtained was taken through an analogous sequence ofreactions to those described in the fifth to seventh paragraphs of theportion of Note [8] immediately above that is concerned with thepreparation of starting materials. There was thus obtained7-(2-acetoxy-3-piperidinopropoxy)-4-chloro-6-methoxyquinazoline; NMRSpectrum: (CDCl₃ and CD₃CO₂D) 1.6 (m, 2H), 1.9 (m, 4H), 2.1 (s, 3H), 3.2(br s, 4H), 3.5 (m, 2H), 4.05 (s, 3H), 4.35 (m, 2H), 5.7 (m, 1H), 7.4(s, 1H), 7.5 (s, 1H), 8.9 (s, 1H).

EXAMPLE 34-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

The sodium salt of 1,1,1,3,3,3-hexamethyldisilazane (1M solution in THF;0.592 ml) was added to a solution of 7-amino-6-chlorobenzofuran (0.099g) in DMF (5 ml) and the reaction mixture was stirred at ambienttemperature for 30 minutes.4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.1 g) was addedand the resultant mixture was stirred at ambient temperature for 3hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was washed in turn with water and brine, dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. The material so obtained was dissolvedin methylene chloride and a 5M solution of hydrogen chloride gas inisopropanol (0.088 ml) was added. Diethyl ether was added and theprecipitate was isolated and dried under vacuum. There was thus obtainedthe title compound (0.118 g) as a dihydrochloride salt; NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 2.35 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.55 (d,2H), 3.75 (t, 2H), 4.0 (m, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.15 (d,1H), 7.45 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.25 (s, 1H),8.8 (s, 1H); Mass Spectrum: M+H⁺ 469.

The 7-amino-6-chlorobenzofuran used as a starting material was preparedas follows:

Sodium hydride (60% dispersion in mineral oil; 4.6 g) was added to astirred solution of 6-chloroanthranilic acid (18 g) in DMF (100 ml) andthe mixture was stirred at ambient temperature for 30 minutes. Ethyliodide (10 ml) was added and the reaction mixture was stirred at ambienttemperature for 2 days. The solvent was evaporated and the residue waspartitioned between ethyl acetate and water. The organic phase waswashed in turn with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and ethylacetate as eluent. There was thus obtained ethyl 6-chloroanthranilate(15.8 g) as an oil; NMR Spectrum: (DMSOd₆) 1.3 (t, 3H), 4.3 (q, 2H), 5.7(br s, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 7.1 (t, 1H).

A solution of sodium nitrite (4.5 g) in water (100 ml) was addeddropwise during 5 minutes to a stirred suspension of ethyl6-chloroanthranilate (12.7 g) in a mixture of concentrated sulphuricacid (27.9 ml), water (38 ml) and ice (76 g). The reaction mixture wasstirred at 0° C. for an additional 20 minutes and then heated to 120° C.for 1 hour. The resultant mixture was poured into a mixture of ice andwater and the product was extracted with diethyl ether. The organicphase was washed in turn with water and brine, dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 4:1 mixture of petroleum ether (b.p.60-80° C.) and methylene chloride as eluent. There was thus obtainedethyl 6-chloro-2-hydroxybenzoate (9.8 g); NMR Spectrum: (DMSOd₆) 1.3 (t,3H), 4.3 (q, 2H), 6.9 (d, 1H), 6.95 (d, 1H), 7.25 (d, 1H), 10.45 (br s,1H).

Allyl bromide (5.5 ml) was added to a stirred mixture of ethyl6-chloro-2-hydroxybenzoate (9.8 g), 1,5,7-triazabicyclo[4,4,0]dec-5-ene(10.4 g) and acetonitrile (250 ml) and the reaction mixture was stirredat ambient temperature for 20 hours. The mixture was evaporated and theresidue was purified by column chromatography on silica using a 17:3mixture of petroleum ether (b.p. 60-80° C.) and diethyl ether as eluent.There was thus obtained ethyl 2-allyloxy-6-chlorobenzoate (10.3 g); NMRSpectrum: (DMSOd₆) 1.3 (t, 3H), 4.35 (q, 2H), 4.65 (d, 2H), 5.25 (d,1H), 5.4 (d, 1H), 6.0 (m, 1H), 7.15 (m, 2H), 7.45 (t, 1H).

The material so obtained was heated to 230° C. for 1 hour. The reactionproduct was cooled to ambient temperature and purified by columnchromatography on silica using a 4:1 mixture of petroleum ether (b.p.60-80° C.) and methylene chloride as eluent. There was thus obtainedethyl 3-allyl-6-chloro-2-hydroxybenzoate (7.3 g); NMR Spectrum: (DMSOd₆)1.3 (t, 3H), 3.3 (m, 2H); 4.35 (q, 2H), 5.05 (m, 2H), 5.95 (m, 1H), 6.95(d, 1H), 7.15 (d, 1H), 9.7 (br s, 1H).

Using analogous procedures to those described in the third paragraph ofthe portion of Note [6] in Example 2 that is concerned with thepreparation of 7-amino-5-fluorobenzofuran, ethyl3-allyl-6-chloro-2-hydroxybenzoate was reacted with ozone and theresultant product,2-(4-chloro-3-ethoxycarbonyl-2-hydroxyphenyl)acetaldehyde, was treatedwith 85% phosphoric acid to give ethyl 6-chlorobenzofuran-7-carboxylate(5.9 g); NMR Spectrum: (DMSOd₆) 1.35 (t, 3H), 4.45 (q, 2H), 7.10 (d,1H), 7.45 (d, 1H), 7.85 (d, 1H), 8.15 (d, 1H).

A mixture of the material so obtained, 35% aqueous potassium hydroxidesolution (12.7 ml) and methanol (20 ml) was stirred and heated to refluxfor 1 hour. The methanol was evaporated and the residue was diluted withwater and acidified to pH1 by the addition of 6N aqueous hydrochloricacid. The resultant precipitate was isolated, washed with water anddried under vacuum over phosphorus pentoxide to give6-chlorobenzofuran-7-carboxylic acid (4.6 g); NMR Spectrum: (DMSOd₆)7.05 (d, 1H), 7.4 (d, 1H), 7.75 (d, 1H), 8.1 (d, 1H).

A mixture of a portion (1 g) of the material so obtained,diphenylphosphoryl azide (2.2 ml), triethylamine (1.4 ml) andtert-butanol (2.7 ml) was stirred and heated to reflux for 18 hours. Themixture was allowed to cool to ambient temperature, poured into waterand extracted with ethyl acetate. The organic phase was washed in turnwith water and brine, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on alumina usingincreasingly polar solvent mixtures starting with mixtures of petroleumether and methylene chloride and ending with a 4:1 mixture of methylenechloride and ethyl acetate. There was thus obtained a mixture of7-amino-6-chlorobenzofuran and tert-butyl6-chlorobenzofuran-7-carbamate. A solution of the mixture so obtained inmethylene chloride (15 ml) was cooled to 0° C. and trifluoroacetic acid(1.2 ml) was added. The resultant mixture was stirred for 1 hour. Themixture was evaporated and the residue was partitioned between ethylacetate and a saturated aqueous sodium bicarbonate solution. The organicphase was dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica using a 3:1 mixture ofpetroleum ether (b.p. 60-80° C.) and methylene chloride as eluent. Therewas thus obtained 7-amino-6-chlorobenzofuran (0.376 g); NMR Spectrum:(DMSOd₆) 5.5 (br s, 2H), 6.85 (m, 2H), 7.1 (d, 1H), 7.95 (d, 1H); MassSpectrum: M+H⁺ 167.

EXAMPLE 44-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline

Using an analogous procedure to that described in Example 3,4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline wasreacted with 7-amino-6-chlorobenzofuran to give the title compound in32% yield as a dihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD)2.35 (m, 2H), 2.9 (s, 3H), 3.4 (br s, 5H), 3.8 (br s, 5H), 4.05 (s, 3H),4.35 (m, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.6 ( 1H), 7.8 (d, 1H), 8.1(d, 1H), 8.3 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 482.

EXAMPLE 54-(3-bromo-6-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline

Using an analogous procedure to that described in Example 3,4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline was reactedwith 7-amino-3-bromo-6-chlorobenzofuran to give the title compound in46% yield as a dihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD)1.9 (m, 2H), 2.05 (m, 2H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.65(m, 2H), 4.05 (s, 3H), 4.35 (m, 2H), 7.4 (s, 1H), 7.7 (m, 2H), 8.25 (s,1H), 8.4 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 530 and 532.

The 7-amino-3-bromo-6-chlorobenzofuran used as a starting material wasprepared as follows:

A mixture of 6-chlorobenzofuran-7-carboxylic acid (0.5 g),diphenylphosphoryl azide (0.58 ml), triethylamine (0.39 ml) andtert-butanol (1.4 ml) was stirred and heated to 95° C. for 6 hours. Themixture was cooled to ambient temperature and poured into water. Theprecipitate was isolated, washed with water and dried under vacuum overphosphorus pentoxide. There was thus obtained tert-butyl6-chlorobenzofuran-7-carbamate (0.665 g); NMR Spectrum: (DMSOd₆) 1.45(s, 9H), 7.0 (d, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 8.05 (d, 1H), 9.0 (brs, 1H).

The material so obtained was dissolved in carbon disulfide (6 ml) andthe solution was cooled to −10° C. A solution of bromine (0.11 ml) incarbon disulfide (0.5 ml) was added dropwise. The reaction mixture wasstirred and allowed to warm to 15° C. The reaction mixture was filteredand the filtrate was evaporated. There was thus obtained to give a gumcontaining a mixture of the cis- and trans-isomers of tert-butyl2,3-dibromo-6-chloro-2,3-dihydrobenzofuran-7-carbamate (0.87 g).

The material so obtained was dissolved in ethanol (35 ml) and thesolution was cooled to 0° C. A 0.8N aqueous potassium hydroxide solution(23 ml) was added and the reaction mixture was stirred at ambienttemperature for 1.5 hours. The mixture was concentrated by evaporation,water was added and the mixture was neutralised by the addition of 6Naqueous hydrochloric acid. The mixture was extracted with diethyl ether.The organic phase was washed with water and with brine, dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using a 3:2 mixture of petroleum ether (b.p.60-80° C.) and methylene chloride as eluent. There was thus obtainedtert-butyl 3-bromo-6-chlorobenzofuran-7-carbamate (0.325 g); NMRSpectrum: (DMSOd₆) 1.45 (s, 9H), 7.45 (d, 1H), 7.5 (d, 1H), 8.4 (s, 1H),9.1 (br s, 1H); Mass Spectrum: M+H⁺ 347.

A solution of the material so obtained in methylene chloride (5 ml) wascooled to 0° C. and trifluoroacetic acid (0.65 ml) was added. Theresultant mixture was allowed to warm to ambient temperature and wasstirred for 6 hours. The mixture was evaporated, water was added and themixture was basified to pH 7.5 by the addition of a saturated aqueoussodium bicarbonate solution. The resultant mixture was extracted withdiethyl ether. The organic phase was washed in turn with water andbrine, dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica using a 3:2 mixture ofpetroleum ether (b.p. 60-80° C.) and methylene chloride as eluent. Therewas thus obtained 7-amino-3-bromo-6-chlorobenzofuran (0.15 g); NMRSpectrum: (DMSOd₆) 5.8 (br s, 2H), 6.7 (d, 1H), 7.2 (d, 1H), 8.3 (s,1H); Mass Spectrum: M+H⁺ 247.

The 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline used as astarting material was prepared as follows:

A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g),3-(pyrrolidin-1-yl)propyl chloride (J. Amer. Chem. Soc., 1955, 77, 2272;14.75 g), potassium carbonate (13.8 g), potassium iodide (1.66 g) andDMF (150 ml) was stirred and heated to 100° C. for 3 hours. The mixturewas allowed to cool to ambient temperature, filtered and the filtratewas evaporated. The residue was dissolved in ethanol (75 ml), 2N aqueoussodium hydroxide solution (75 ml) was added and the mixture was heatedto 90° C. for 2 hours. The mixture was concentrated by evaporation andacidified by the addition of concentrated aqueous hydrochloric acid. Theresultant mixture was washed with diethyl ether and then purified bycolumn chromatography using a Diaion (trade mark of Mitsubishi) HP20SSresin column, eluting with water and then with a gradient of methanol (0to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed byevaporation and the aqueous residue was freeze dried to give3-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzoic acid hydrochloride (12.2g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 2.2 (m, 2H), 3.15 (t, 2H), 3.3(t, 2H), 3.5 (d, 2H), 3.7 (t, 2H), 3.82 (s, 3H), 4.05 (d, 2H), 4.15 (t,2H), 7.07 (d, 1H), 7.48 (s, 1H), 7.59 (d, 1H).

The material so obtained was dissolved in trifluoroacetic acid (40 ml)and the solution was cooled to 0° C. Fuming nitric acid (2.4 ml) wasadded slowly. The cooling bath was removed and the reaction mixture wasstirred at ambient temperature for 1 hour. The mixture was evaporatedand a mixture of ice and water was added to the residue. The mixture wasevaporated. The solid residue was dissolved in dilute hydrochloric acid(pH2.2) and purified by column chromatography using a Diaion HP20SSresin column using a gradient of methanol (0 to 50%) in water.Concentration of the fractions by evaporation gave a precipitate whichwas collected and dried under vacuum over phosphorus pentoxide. Therewas thus obtained 5-methoxy-2-nitro-4-(3-pyrrolidin-1-ylpropoxy)benzoicacid hydrochloride (12.1 g, 90%); NMR Spectrum: (DMSOd₆ and CF₃CO₂D)1.8-1.9 (m, 2H), 2.0-2.1 (m, 2H), 2.1-2.2 (m, 2H), 3.0-3.1 (m, 2H), 3.3(t, 2H), 3.6-3.7 (m, 2H), 3.95 (s, 3H), 4.25 (t, 2H), 7.35 (s, 1H), 7.62(s, 1H).

A mixture of a portion (9.63 g) of the material so obtained, thionylchloride (20 ml) and DMF (0.05 ml) was heated to 45° C. for 1.5 hours.The excess thionyl chloride was evaporated using the evaporation ofadded toluene (×2) to remove the last traces. The resultant solid wassuspended in a mixture of THF (250 ml) and methylene chloride (100 ml)and ammonia was bubbled though the mixture for 30 minutes. The resultantmixture was stirred for a further 1.5 hours at ambient temperature. Thevolatiles were removed by evaporation and the residue was dissolved inwater and purified by column chromatography using a Diaion HP20SS resincolumn eluting with a gradient of methanol (0 to 5%) in water. Thesolvent was removed by evaporation from the fractions containingproduct. The residue was dissolved in a minimum of methanol and thesolution was diluted with diethyl ether. The resultant precipitate wascollected by filtration, washed with diethyl ether and dried undervacuum to give 5-methoxy-2-nitro-4-(3-pyrrolidin-1-ylpropoxy)benzamide(7.23 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.85-1.95 (m, 2H), 2-2.1(m, 2H), 2.15-2.25 (m, 2H), 3.0-3.1 (m, 2H), 3.31 (t, 2H), 3.62 (t, 2H),3.93 (s, 3H), 4.2 (t, 2H), 7.16 (s, 1H), 7.6 (s, 1H).

A mixture of a portion (1.5 g) of the material, so obtained,concentrated aqueous hydrochloric acid (5 ml) and methanol (20 ml) waswarmed to 50° C. to give a solution. Iron powder (1.3 g) was added inportions and the reaction mixture was heated to reflux for 1 hour. Themixture was allowed to cool to ambient temperature. Insoluble materialwas removed by filtration through diatomaceous earth and the filtratewas evaporated. The residue was purified by column chromatography usinga Diaion HP20SS resin column, eluting with water and then with diluteaqueous hydrochloric acid (pH2). The fractions containing product wereconcentrated by evaporation and the resultant precipitate was collectedby filtration and dried under vacuum over phosphorus pentoxide. Therewas thus obtained2-amino-5-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzamide hydrochloride(1.44 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9 (br s, 2H), 2.05 (br s,2H), 2.2 (br s, 2H), 3.05 (br s, 2H), 3.3 (t, 2H), 3.61 (br s, 2H), 3.8(s, 3H), 4.11 (t, 2H), 7.05 (s, 1H), 7.53 (s, 1H).

After repetition of the previous reaction, a mixture of2-amino-5-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzamide hydrochloride(5.92 g), Gold's reagent (3.5 g) and dioxane (50 ml) was heated toreflux for 5 hours. Acetic acid (0.7 ml) and sodium acetate (1.33 g)were added and the reaction mixture was heated to reflux for a further 5hours. The mixture was allowed to cool to ambient temperature andevaporated. The residue was dissolved in water, adjusted to pH8 with 2Naqueous sodium hydroxide solution and purified on a Diaion HP20SS resincolumn eluting with methanol (gradient 0-50%) in water. The fractionscontaining product were concentrated by evaporation and then freezedried to give6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-3,4-dihydroquinazolin-4-one (4.55g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9 (m, 2H), 2.0-2.1 (m, 2H),2.2-2.3 (m, 2H), 3.05 (m, 2H), 3.34 (t, 2H), 3.6-3.7 (br s, 2H), 3.94(s, 3H), 4.27 (t, 2H), 7.31 (s, 1H), 7.55 (s, 1H), 9.02 (s, 1H).

A mixture of a portion (1.7 g) of the material so obtained, thionylchloride (25 ml) and DMF (0.2 ml) was heated at reflux for 3 hours.Excess thionyl chloride was removed by evaporation and by azeotropingwith toluene (×2). The residue was suspended in diethyl ether and washedwith a 10% aqueous solution of sodium bicarbonate. The organic layer wasdried over magnesium sulphate and evaporated to give4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (1.94 g); NMRSpectrum: (CDCl₃) 1.8 (br s, 4H), 2.17 (m, 2H), 2.6 (br s, 4H), 2.7 (t,2H), 4.05 (s, 3H), 4.3 (t, 2H), 7.35 (s, 1H), 7.38 (s, 1H), 8.86 (s,1H).

EXAMPLE 64-(3-chlorobenzofuran-7-ylamino)-7-(2-hydroxy-3-morpholinopropoxy)-6-methoxyquinazolinedihydrochloride salt

A mixture of7-(2-acetoxy-3-morpholinopropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazolinedihydrochloride (0.15 g) and a saturated methanolic ammonia solution (3ml) was stirred at ambient temperature overnight. The solvent wasevaporated and the residue was dissolved in methylene chloride (3 ml)and adsorbed to the top of a pre-packed silica column (NH₂-silica;Isolute sorbent from International Sorbent Technology Ltd, ref. no.9470-0100) and eluted with a 19:1 mixture of methylene chloride andmethanol. The material so obtained was dissolved in methylene chloride(3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml)was added. Diethyl ether (10 ml) was added and the resultant precipitatewas collected by filtration, washed with diethyl ether and dried undervacuum. There was thus obtained the title compound (0.11 g); MassSpectrum: M+H⁺ 486.

EXAMPLE 7

Using an analogous procedure to that described in Example 6, theappropriate 7-(2-acetoxypropoxy)quinazoline was reacted with a saturatedmethanolic ammonia solution to give the compounds described in Table II.Unless otherwise stated, each compound described in Table II wasobtained as a dihydrochloride salt.

TABLE II

No. R¹ R² Note 1 2-hydroxy-3-(N-isopropyl-N-methylamino)- 3-chloro [1]propoxy 2 3-(4-cyanomethylpiperazin-1-yl)-2-hydroxy- 3-chloro [2]propoxy 3 2-hydroxy-3-pyrrrolidin-1-ylpropoxy 3-chloro [3] 42-hydroxy-3-piperidinopropoxy 3-chloro [4] Notes [1] The product gavethe following characterising data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D):1.21-1.37 (m, 6H), 2.81 (s, 3H), 3.12-3.5 (m, 2H), 3.56-3.74 (m, 1H),4.05 (s, 3H), 4.33-4.32 (m, 2H), 4.4-4.5 (m, 1H), 7.46 (d, 1H), 7.55 (t,1H), 7.6 (d, 1H), 7.71 (m, 1H), 8.29 (s, 1H), 8.38 (s, 1H), 8.84 (s,1H); Mass Spectrum: M + H⁺ 471. [2] The product gave the followingcharacterising data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D): 2.64-2.88 (m,2H), 2.89-3.1 (m, 2H), 3.13-3.48 (m, 4H), 3.54-3.74 (m, 2H), 3.88 (s,2H), 4.05 (s, 3H), 4.21-4.32 (m, 2H), 4.48-4.58 (m, 1H), 7.51 (s, 1H),7.54 (t, 1H), 7.6 (m, 1H), 7.7 (m, 1H), 8.36 (s, 1H), 8.38 (s, 1H), 8.83(s, 1H); Mass Spectrum: M + H⁺ 523. [3] The product gave the followingcharacterising data: NMR Spectrum: (DMSOD₆ and CF₃CO₂D): 1.87-1.99 (m,2H), 2.0-2.1 (m, 2H), 3.1-3.22 (m, 2H), 3.4 (d, 2H), 3.6-3.7 (m, 2H),4.04 (s, 3H), 4.25 (d, 2H), 4.35-4.45 (m, 1H), 7.45 (s, 1H), 7.54 (t,1H), 7.60 (m, 1H), 7.71 (m, 1H), 8.28 (s, 1H), 8.38 (s, 1H), 8.84 (s,1H); Mass Spectrum: M + H⁺ 469. [4] The product gave the followingcharacterising data: NMR Spectrum: (DMSOD₆ and CF₃CO₂D): 1.36-1.52 (m,1H), 1.66-1.93 (m, 5H), 2.93-3.13 (m, 2H), 3.21-3.4 (m, 2H), 3.48-3.64(m, 2H), 4.06 (s, 3H), 4.26 (d, 2H), 4.48-4.59 (m, 1H), 7.5 (s, 1H),7.54 (t, 1H), 7.6 (m, 1H), 7.7 (m, 1H), 8.34 (s, 1H), 8.37 (s, 1H), 8.84(s, 1H); Mass Spectrum: M + H⁺ 483.

EXAMPLE 84-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-piperidin-4-ylmethoxyquinazoline

A mixture of7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline(0.4 g), trifluoroacetic acid (3 ml) and methylene chloride (12 ml) wasstirred at ambient temperature for 3 hours. The mixture was evaporatedand the residue was diluted with water. The mixture was basified to pH11by the addition of 1 N aqueous sodium hydroxide solution and methylenechloride was added. The precipitate which was formed was collected byfiltration, washed with water and dried under vacuum to give the titlecompound (0.195 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.55 (m, 2H), 2.0(m, 2H), 2.25 (m, 1H), 2.95 (m, 2H), 3.4 (m, 2H), 4.05 (s, 3H), 4.2 (d,2H), 7.1 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.05 (d, 1H),8.2 (s, 1H), 8.85 (s, 1H), Mass Spectrum: M−H⁻ 437.

The7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazolineused as a starting material was prepared as follows:

The sodium salt of 1,1,1,3,3,3-hexamethyldisilazane (66 ml, 1M solutionin THF) was added dropwise to 7-amino-6-chlorobenzofuran (11.0 g) insolution in DMF (170 ml) and the mixture was stirred at ambienttemperature for 30 minutes. A solution of7-benzyloxy-4-chloro-6-methoxyquinazoline (9.8 g) in DMF (200 ml) wasadded and the reaction mixture was stirred at ambient temperature for 24hours. The solvent was evaporated and the residue was partitionedbetween methylene chloride and water. The organic phase was washed withwater and with brine, dried over magnesium sulphate and evaporated. Thematerial so obtained was purified by column chromatography on silicausing increasingly polar mixtures of methylene chloride and methanol.There was thus obtained7-benzyloxy-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline (12.0g) as a solid; NMR Spectrum: (DMSOd₆) 3.95 (s, 3H), 5.3 (s, 2H), 7.05(s, 1H), 7.3 (s, 1H), 7.35-7.55 (m, 6H), 7.65 (d, 1H), 7.95 (s, 1H), 8.0(d, 1H), 8.25 (s, 1H), 9.75 (s, 1H); Mass Spectrum: M+H⁺ 432 and 434.

A mixture of the material so obtained and trifluoroacetic acid (120 ml)was heated to reflux for 5 hours. The solvent was evaporated, toluenewas added and the solvent was evaporated again. The residue was dilutedwith water and the pH was adjusted to 8 with a saturated aqueoussolution of sodium bicarbonate. Methylene chloride (150 ml) was addedwhich caused the desired product to precipitate. The solid was collectedby filtration, washed with water and dried under vacuum to give the4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (9.5 g);NMR Spectrum: (DMSOd₆) 4.0 (s, 3H), 7.1 (s, 1H), 7.15 (s, 1H), 7.5 (d,1H), 7.7 (d, 1H), 8.0 (m, 2H), 8.4 (br s, 1H); Mass Spectrum: M+H⁺ 342.

N-(tert-Butoxycarbonyl)-4-(4-toluenesulphonyloxymethyl)piperidine (0.388g) was added to a mixture of4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (0.3 g),potassium carbonate (0.484 g) and DMF (4 ml) and the mixture was heatedto 55° C. for 4 hours and to 80° C. for 3 hours. The excess potassiumcarbonate was removed by filtration. The filtrate was evaporated and theresidue was partitioned between ethyl acetate and water. The organicphase was washed with water and with brine, dried over magnesiumsulphate and evaporated. The material so obtained was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline(0.405 g); Mass Spectrum: M−H⁻ 537.

The N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine usedas a starting material was prepared as follows:

A solution of di-tert-butyl dicarbonate (41.7 g) in ethyl acetate (75ml) was added dropwise to a stirred solution of ethyl piperidine4-carboxylate (30 g) in ethyl acetate (150 ml) which had been cooled to0 to 5° C. in an ice-bath. The resultant mixture was stirred at ambienttemperature for 48 hours. The mixture: was poured into water (300 ml).The organic layer was separated, washed in turn with water (200 ml),0.1N aqueous hydrochloric acid solution (200 ml), a saturated aqueoussodium bicarbonate solution (200 ml) and brine (200 ml), dried overmagnesium sulphate and evaporated. There was thus obtained ethylN-tert-butoxycarbonylpiperidine-4-carboxylate (48 g); NMR Spectrum:(CDCl₃) 1.25 (t, 3H), 1.45 (s, 9H), 1.55-1.7 (m, 2H), 1.8-2.0 (d, 2H),2.35-2.5 (m, 1H), 2.7-2.95 (t, 2H), 3.9-4.1 (br s, 2H), 4.15 (q, 2H).

A solution of the material so obtained in THF (180 ml) was cooled at 0°C. and lithium aluminium hydride (1M solution in THF; 133 ml) was addeddropwise. The mixture was stirred at 0° C. for 2 hours. Water (30 ml)and 2N aqueous sodium hydroxide solution (10 ml) were added in turn andthe mixture was stirred for 15 minutes. The resultant mixture wasfiltered through diatomaceous earth and the solids were washed withethyl acetate. The filtrate was washed in turn with water and withbrine, dried over magnesium sulphate and evaporated. There was thusobtained N-tert-butoxycarbonyl-4-hydroxymethylpiperidine (36.3 g); NMRSpectrum: (CDCl₃) 1.05-1.2 (m, 2H), 1.35-1.55 (m, 10H), 1.6-1.8 (m, 2H),2.6-2.8 (t, 2H), 3.4-3.6 (t, 2H), 4.0-4.2 (br s, 2H).

1,4-Diazabicyclo[2.2.2]octane (42.4 g) was added to a solution ofN-tert-butoxycarbonyl-4-hydroxymethylpiperidine (52.5 g) in tert-butylmethyl ether (525 ml) and the mixture was stirred at ambient temperaturefor 15 minutes. The mixture was then cooled in an ice-bath to 5° C. anda solution of 4-toluenesulphonyl chloride (62.8 g) in tert-butyl methylether (525 ml) was added dropwise over 2 hours while maintaining thereaction temperature at approximately 0° C. The resultant mixture wasallowed to warm to ambient temperature and was stirred for 1 hour.Petroleum ether (b.p. 60-80° C., 1 L) was added and the precipitate wasremoved by filtration. The filtrate was evaporated to give a solidresidue which was dissolved in diethyl ether. The organic solution waswashed in turn with 0.5N aqueous hydrochloric acid solution, water, asaturated aqueous sodium bicarbonate solution and brine, dried overmagnesium sulphate and evaporated. There was thus obtainedN-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine (76.7g); NMR Spectrum: (CDCl₃) 1.0-1.2 (m, 2H), 1.45 (s, 9H), 1.65 (d, 2H),1.75-1.9 (m, 2H), 2.45 (s, 3H), 2.55-2.75 (m, 2H), 3.85 (d, 1H), 4.0-4.2(br s, 2H), 7.35 (d, 2H), 7.8 (d, 2H).

EXAMPLE 94-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(1-methylpiperazin-4-ylmethoxy]quinazoline

(6-Chlorobenzofuran-7-ylamino)-6-methoxy-7-piperidin-4-ylmethoxyquinazoline(0.22 g) was dissolved in methylene chloride (17 ml). Formaldehyde (37%aqueous solution; 0.089 ml) and sodium triacetoxyborohydride (0.149 g)were added in turn followed by methanol (5 ml). The reaction mixture wasstirred at ambient temperature for 1 hour. A saturated aqueous solutionof sodium bicarbonate (10 ml) was added and the product was extractedwith methylene chloride. The organic phase was washed with water andwith brine, dried over magnesium sulphate and evaporated. The crudeproduct was purified by column chromatography on silica usingincreasingly polar solvent mixtures of methylene chloride and asaturated methanolic ammonia solution. The material so obtained wastriturated under diethyl ether. There was thus obtained the titlecompound; NMR Spectrum: (DMSOd₆) 1.5 (m, 2H), 1.9 (m, 3H), 2.4 (m, 5H),3.1 (m, 2H), 3.95 (s, 3H), 4.05 (d, 2H), 7.05 (d, 1H), 7.2 (s, 1H), 7.45(d, 1H), 7.65 (d, 1H), 7.9 (s, 1H), 8.0 (s, 1H), 8.25 (s, 1H), 9.75 (s,1H); Mass Spectrum: M+H⁺ 453.

EXAMPLE 104-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline

Diethyl azodicarboxylate (0.101 ml) was added dropwise to a stirredmixture of4-(⁶-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (0.1 g),1-(2-hydroxyethyl)pyrrolidine (0.04 g), triphenylphosphine (0.169 g) andmethylene chloride (5 ml) and the reaction mixture was stirred atambient temperature for 2 hours. The solvent was evaporated and theresidue was purified by column chromatography on silica usingincreasingly polar mixture of methylene chloride and a saturatedmethanolic ammonia solution as eluent. There was thus obtained the titlecompound (0.033 g) as a solid; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9(m, 2H), 2.1 (m, 2H), 3.2 (m, 2H), 3.65-3.85 (m, 4H), 4.05 (s, 3H), 4.6(m, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.6 (d, 1H), 7.8 (d, 1H), 8.1 (d,1H), 8.25 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 439.

EXAMPLE 11

Using an analogous procedure to that described in Example 10, theappropriate alcohol was reacted with4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline to givethe compounds described in Table III.

TABLE III

No. R¹ R² Note 1 3-pyrrolidin-1-ylpropoxy 6-chloro [1] 22-piperidinoethoxy 6-chloro [2] 3 2-(4-methylpiperazin-1-yl)ethoxy6-chloro [3] Notes [1] The product gave the following characterisingdata: NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9 (m, 2H), 2.05 (m, 2H), 2.25(m, 2H), 3.1 (m, 2H), 3.35 (m, 2H), 3.65 (m, 2H), 4.05 (s, 3H), 4.35 (m,2H), 7.15 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.05 (d, 1H),8.2 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M − H⁻ 451. [2] The productgave the following data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.4 (m, 1H),1.7 (m, 3H), 1.9 (m, 2H), 3.1 (m, 2H), 3.6 (m, 2H), 3.7 (m, 2H), 4.05(s, 3H), 4.65 (t, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.6 (d, 1H), 7.8 (d,1H), 8.1 (d, 1H), 8.25 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M − H⁻ 451.[3] The product gave the following characterising data; NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 2.9 (s, 3H), 3.3-3.9 (m, 10H), 4.05 (s, 3H), 4.6(m, 2H), 7.15 (d, 1H), 7.5 (s, 1H), 7.6 (d, 1H), 7.8 (d, 1H), 8.1 (d,1H), 8.25 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M − H⁻ 466.

EXAMPLE 124-(6-chlorobenzofuran-7-ylamino)-7-[(2R)-2-hydroxy-3-piperidinopropoxy]-6-methoxyquinazolinedihydrochloride salt

A mixture of4-(6-chlorobenzofuran-7-ylamino)-7-[(2R)-2,3-epoxypropoxy]-6-methoxyquinazoline(0.1 g), piperidine (2.5 mole equivalents), chloroform (2.5 ml) andethanol (2.5 ml) was heated to 40° C. for 8 hours. The solvent wasevaporated under reduced pressure. Methylene chloride (5 ml) was addedfollowed by a polystyrene isocyanate resin (0.3 g; loading: 1 mmol/g;prepared according to J. Amer. Chem. Soc., 1997, 119, 4882) and themixture was shaken for 1.5 hours at ambient temperature. The resin wasremoved by filtration and washed with methylene chloride. The solventwas evaporated and the crude product was purified by columnchromatography on silica using increasingly polar mixture of methylenechloride and a saturated methanolic ammonia solution as eluent. Thematerial so obtained was dissolved in a 9:1 mixture (3 ml) of methylenechloride and methanol and a 2.2M solution of hydrogen chloride indiethyl ether (1 ml) was added. The resultant precipitate was collectedby filtration and dried under vacuum to give the desired product as adihydrochloride salt (0.09 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D)1.35-1.5 (m, 1H), 1.65-1.92 (m, 5H), 2.93-3.13 (m, 2H), 3.21-3.39(m,2H), 3.48-3.61 (m, 2H), 4.05 (s, 3H), 4.26 (d, 2H), 4.47-4.56 (m, 1H),7.11 (d, 1H), 7.49 (s, 1H), 7.56 (d, 1H), 7.78 (d, 1H), 8.06 (d, 1H),8.32 (s, 1H), 8.83(s, 1H); Mass Spectrum: M+H⁺ 483.

The4-(6-chlorobenzofuran-7-ylamino)-7-[(2R)-2,3-epoxypropoxy]-6-methoxyquinazolineused as a starting material was prepared as follows:

A mixture of4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (5.0 g),(2R)-(−)glycidyl tosylate (4 g), potassium carbonate (8 g) and DMF (60ml) was heated to 55° C. for 4 hours. The excess potassium carbonate wasremoved by filtration and washed with ethyl acetate. The combinedsolvents were evaporated and the residue was partitioned between amixture of ethyl acetate and acetonitrile and water. The organic phasewas washed in turn with a 5% aqueous ammonium hydroxide solution, waterand brine, dried over magnesium sulphate and evaporated. The resulatantfoam was suspended in methylene chloride and diethyl ether was added toform a precipitate which was collected by filtration and dried undervacuum. There was thus obtained the desired product (4.6 g); NMRSpectrum: (DMSOd₆) 2.75 (m, 1H); 2.9 (m, 1H); 3.45 (m, 1H); 4.0 (s, 3H);4.55 (m, 1H); 7.05 (s, 1H); 7.25 (s, 1H); 7.5 (d, 1H); 7.65 (d, 1H);7.95 (s, 1H); 8.0 (s, 1H); 8.25 (s, 1H); 9.8 (s, 1H).

EXAMPLE 13

Using an analogous procedure to that described in Example 12, theappropriate amine was reacted with4-(6-chlorobenzofuran-7-ylamino)-7-[(2R)-2,3-epoxypropoxy]-6-methoxyquinazolineto give the compounds described in Table IV.

TABLE IV

No. R¹ R² Note 1 (2R)-2-hydroxy-3-pyrrolidin-1-ylpropoxy 6-chloro [1] 2(2R)-2-hydroxy-3-N-isopropyl-N-methylamino)- 6-chloro [2] propoxy 3(2R)-3-(N-allyl-N-methylamino)-2-hydroxy- 6-chloro [3] propoxy 4(2R)-3-homopiperidin-1-yl-2-hydroxypropoxy 6-chloro [4] 53-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1- 6-chloro [5]yl]-(2R)-2-hydroxypropoxy 6 (2R)-2-hydroxy-3-(N-isobutyl-N-methylamino)-6-chloro [6] propoxy Notes [1] The product gave the followingcharacterising data; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.86-1.98 (m,2H), 1.99-2.12 (m, 2H), 3.08-3.21 (m, 2H), 3.34-3.45 (m, 2H), 3.6-3.71(m, 2H), 4.06 (s, 3H), 4.26 (d, 2H), 4.37-4.46 (m, 1H), 7.12 (d, 1H),7.50 (s, 1H), 7.56 (d, 1H), 7.79 (d, 1H), 8.06 (d, 1H), 8.34 (s, 1H),8.82 (s, 1H); Mass Spectrum: M + H⁺ 469. [2] The product gave thefollowing characterising data; NMR Spectrum: (DMSOd₆ and CF₃CO₂D)1.21-1.38 (m, 6H), 2.81(s, 3H), 3.09-3.67(m, 3H), 4.06 (s, 3H),4.22-4.33 (m, 2H), 4.38-4.52 (m, 1H), 7.13 (d, 1H), 7.48 (d, 1H), 7.57(d, 1H), 7.79 (d, 1H), 8.07 (d, 1H), 8.31 (s, 1H); 8.84 (s, 1H); MassSpectrum: M + H⁺ 471. [3] The product gave the following characterisingdata; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 2.86 (br s, 3H), 3.18-3.46 (m,2H), 3.75-3.99 (m, 2H), 4.06 (s, 3H), 4.22-4.33 (m, 2H), 4.43-4.57 (m,1H), 5.5-5.6 (m, 2H), 6.0 (m, 1H), 7.12 (d, 1H), 7.51 (s, 1H), 7.56 (d,1H), 7.79 (d, 1H), 8.07 (d, 1H), 8.36 (s, 1H), 8.83 (s, 1H); MassSpectrum: M + H⁺ 469. [4] The product gave the following characterisingdata; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.54-1.74 (m, 4H), 1.75-1.98(m, 4H), 3.17-3.34 (m, 3H), 3.38-3.55 (m, 3H), 4.06 (s, 3H), 4.26 (d,2H), 4.42-4.52 (m, 1H), 7.13 (d, 1H), 7.48 (s, 1H), 7.57 (d, 1H), 7.8(d, 1H), 8.08 (d, 1H), 8.29 (s, 1H), 8.84 (s, 1H); Mass Spectrum: M + H⁺497. [5] The product gave the following characterising data; NMRSpectrum: (DMSOd₆ and CF₃CO₂D) 1.75-2.0 (m, 2H), 2.06-2.2 (m, 1H),2.54-2.64 (m, 1H), 2.95 (s, 3H), 3.01 (s, 3H), 3.22-3.37 (m, 2H),3.46-3.54 (m, 1H), 3.84-3.95 (m, 1H), 4.05 (s, 3H), 4.18-4.3 (m, 2H),4.39-4.5 (m, 1H), 4.83 (t, 1H), 7.13 (d, 1H), 7.45 (s, 1H), 7.57 (d,1H), 7.79 (d, 1H), 8.07 (d, 1H), 8.29 (s, 1H), 8.83 (s, 1H); MassSpectrum: M + H⁺ 540. [6] The product gave the following characterisingdata; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 0.94-1.09 (m, 6H), 2.04-2.26(m, 1H), 2.95 (s, 3H), 2.96-3.05 (m, 1H), 3.08-3.33 (m, 2H), 3.34-3.47(m, 1H), 4.07 (s, 3H), 4.21-4.34 (m, 2H), 4.46-4.61 (m, 1H), 7.13 (d,1H), 7.52 (s, 1H), 7.57 (d, 1H), 7.79 (d, 1H), 8.08 (d, 1H), 8.36 (s,1H), 8.84 (s, 1H); Mass Spectrum: M + H⁺ 485.

EXAMPLE 147-[2-N-tert-butoxycarbonylpiperidin-4-yl)ethoxy]4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline

Diethyl azodicarboxylate (0.304 ml) was added dropwise to a stirredmixture of4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (0.3 g),2-(N-tert-butoxycarbonylpiperidin-4-yl)ethanol [International PatentApplication WO 00/47212 (within Example 126 thereof); 0.221 g],triphenylphosphine (0.506 g) and methylene chloride (20 ml) and thereaction mixture was stirred at ambient temperature for 3 hours. Thesolvent was removed by evaporation and the residue was purified bycolumn chromatography on silica using increasingly polar solventmixtures of methylene chloride and acetonitrile. There was thus obtainedthe title compound (0.49 g); Mass Spectrum: M+H⁺ 553 and 555.

EXAMPLE 154-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(2-piperidin-4-ylethoxy)quinazoline

A mixture of7-[2-(N-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline(0.49 g), trifluoroacetic acid (4 ml) and methylene chloride (15 ml) wasstirred at ambient temperature for 3 hours. The solvents were evaporatedand the residue was diluted with toluene and evaporated again. Theresidue was partitioned between a mixture of methylene chloride andacetonitrile and a 2N aqueous sodium hydroxide solution. The organicphase was washed with water and with brine, dried over magnesiumsulphate and evaporated. The material so obtained was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand a saturated methanolic ammonia solution. The material so obtainedwas triturated under diethyl ether to give the title compound (0.296 g);NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.4 (m, 2H), 1.75-1.95 (m, 5H), 2.9(m, 2H), 3.3 (m, 2H), 4.05 (s, 3H), 4.3 (m, 2H), 7.15 (d, 1H), 7.4 (s,1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.2 (s, 1H), 8.8 (s, 1H),Mass Spectrum: M+H⁺ 453.

EXAMPLE 164-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-[2-(N-methylpiperazin-4-yl)ethoxy]quinazoline

Using an analogous procedure to that described in Example 9,4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(2-piperidin-4-ylethoxy)quinazoline(0.246 g) was reacted with formaldehyde to give the title compound(0.122 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.45 (m, 2H), 1.8 (m, 3H),2.0 (m, 2H), 2.8 (s, 3H), 2.95 (m, 2H), 3.45 (m, 2H), 4.05 (s, 3H), 4.3(t, 2H), 7.15 (d, 1H), 7.4 (s, 1H), 7.6 (d, 1H), 7.8 (d, 1H), 8.1 (d,1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 467.

EXAMPLE 174-(3-bromo-6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

Using an analogous procedure to that described in Example 3,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.13 g) wasreacted with 7-amino-3-bromo-6-chlorobenzofuran (0.186 g) to give thetitle compound (0.14 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 2.3 (m, 2H),3.15 (m, 2H), 3.35 (t, 2H), 3.55 (m, 2H), 3.7 (t, 2H), 4.0 (s, 3H), 4.05(m, 2H), 4.35 (t, 2H), 7.4 (s, 1H), 7.7 (d, 2H), 8.2 (s, 1H), 8.4 (s,1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 549.

EXAMPLE 18 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5(e) Injection I (50 mg/ml) Compound X 5.0% w/v 1 M Sodium hydroxidesolution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to 100%(g) Injection III (1 mg/ml, buffered to pH 6) Compound X  0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400  3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml Note The above formulations may be obtained by conventionalprocedures well known in the pharmaceutical art. The tablets (a)-(c) maybe enteric coated by conventional means, for example to provide acoating of cellulose acetate phthalate. The aerosol formulations (h)-(k)may be used in conjunction with standard, metered dose aerosoldispensers, and the suspending agents sorbitan trioleate and soyalecithin may be replaced # by an alternative suspending agent such assorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerololeate or oleic acid.

1. A quinazoline derivative of the Formula I

wherein m is 0, 1, 2 or 3; each R¹ group, which may be the same ordifferent, is selected from halogeno, trifluoromethyl, cyano, isocyano,nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:Q¹—X¹—  wherein X¹ is a direct bond or is selected from O, S, SO, SO₂,N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂,SC(⁴)₂ and N(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or (1-6C)alkyl, and Q¹ isaryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or(R¹)_(m) is (1-3C)alkylenedioxy, and wherein adjacent carbon atoms inany (2-6C)alkylene chain within a R¹ substituent are optionallyseparated by the insertion into the chain of a group selected from O, S,SO, SO₂, N(R⁵), CO, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CHand C≡C wherein R⁵ is hydrogen or (1-6C)alkyl or, when the insertedgroup is N(R⁵), R⁵ may also be (2-6C)alkanoyl, and wherein any CH₂═CH—or HC≡C— group within a R¹ substituent optionally bears at the terminalCH₂═ or HC≡ position a substituent selected from halogeno, carboxy,carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:Q²—X²—  wherein X² is a direct bond or is selected from CO and N(R⁶)CO,wherein R⁶ is hydrogen or (1-6C)alkyl, and Q² is aryl, aryl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein any CH₂ or CH₃ group within a R¹substituent optionally bears on each said CH₂ or CH₃ group one or morehalogeno or (1-6C)alkyl substituents or a substituent selected fromhydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylaminoN-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:—X³—Q³  wherein X³ is a direct bond or is selected from O, S, SO, SO₂,N(R⁷), CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O,C(R⁷)₂S and N(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1-6C)alkyl, and Q³is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,heteroaryl or heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:—X⁴—R⁸  wherein X⁴ is a direct bond or is selected from O and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)-alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:—X⁵—Q⁴  wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) andCO, wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁴ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, and wherein anyheterocyclyl group within a substituent on R¹ optionally bears 1 or 2oxo or thioxo substituents; R² is hydrogen or (1-6C)alkyl; n is 0, 1, 2or 3; and R³ is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:—X⁶—R¹¹  wherein X⁶ is a direct bond or is selected from O and N(R¹²),wherein R¹² is hydrogen or (1-6C)alkyl, and R¹¹ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:—X⁷—Q⁵  wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹³), CO, CH(OR¹³), CON(R¹³), N(R¹³)CO, SO₂N(R¹³), N(R¹³)SO₂,C(R¹³)₂O, C(R¹³)₂S and N(R¹³)C(R¹³)₂, wherein R¹³ is hydrogen or(1-6C)alkyl, and Q⁵ is aryl, aryl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl whichoptionally bears 1 or 2 substituents, which may be the same ordifferent, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl and (1-6C)alkoxy, and any heterocyclyl group within Q⁵optionally bears 1 or 2 oxo or thioxo substituents, or apharmaceutically acceptable salt thereof.
 2. A quinazoline derivative ofthe Formula I according to claim 1 wherein: m is 1 or 2 and each R¹group, which may be the same or different, is located at the 6- and/or7-positions and is selected from hydroxy, amino, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino,ethylamino, dimethylamino, diethylamino, acetamido, propionamido,2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 4-morpholinobutoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and whereinadjacent carbon atoms in any (2-6C)alkylene chain within a R¹substituent are optionally separated by the insertion into the chain ofa group selected from O, NH, CH═CH and C≡C, and wherein any CH₂ or CH₃group within a R¹ substituent optionally bears on each said CH₂ or CH₃group a substituent selected from hydroxy, amino, methoxy,methylsulphonyl, methylamino, dimethylamino, diethylamino,N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylaminoand acetoxy; and wherein any heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R¹substituent is optionally N-substituted with 2-methoxyethyl,3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl,2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, thelast 8 of which substituents each optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro, methyland methoxy, and wherein any heterocyclyl group within a substituent onR¹ optionally bears 1 or 2 oxo substituents; R² is hydrogen; n is 0 or 1and the R³ group, if present, is located at the 5- or 6-position of thebenzofuran ring and is selected from fluoro, chloro, trifluoromethyl,cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy andethoxy; or a pharmaceutically acceptable acid-addition salt thereof. 3.A quinazoline derivative of the Formula I according to claim 1 wherein:m is 2 and the first R¹ group is located at the 6-position and isselected from hydroxy, methoxy, ethoxy and propoxy, and the second R¹group is located at the 7-position and is selected from2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy,2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy,2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy,4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,3-(N-isopropyl-N-methylamino)propoxy,4-(N-isopropyl-N-methylamino)butoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 4-morpholinobutoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy,piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy,3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy,2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,4-(4-methylpiperazin-1-yl)butoxy, 2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,4-(4-cyanomethylpiperazin-1-yl)butoxy,2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy, 2-methylsulphonylethoxy and3-methylsulphonylpropoxy, and wherein any CH₂ group within the second R¹group that is attached to two carbon atoms optionally bears a hydroxygroup or acetoxy group on said CH₂ group, and wherein any heterocyclylgroup within the second R¹ group optionally bears 1 or 2 oxosubstituents; R² is hydrogen; and n is 0 or n is 1 and the R³ group islocated at the 5- or 6-position of the benzofuran ring and is selectedfrom fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, ethynyl,methoxy and ethoxy; or a pharmaceutically acceptable acid-addition saltthereof.
 4. A quinazoline derivative of the Formula I according to claim1 wherein: m is 2 and the first R¹ group is located at the 6-positionand is selected from hydroxy, methoxy, ethoxy and propoxy, and thesecond R¹ group is located at the 7-position and is selected from2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylaminoethoxy,3-diethylaminopropoxy, 2-diisopropylaminoethoxy,3-diisopropylaminopropoxy, 2-(N-isopropyl-N-methylamino)ethoxy,3-(N-isopropyl-N-methylamino)propoxy,2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy,2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 3-homopiperidinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy and3-(4-cyanomethylpiperazin-1-yl)propoxy, and wherein any CH₂ group withinthe second R¹ group that is attached to two carbon atoms optionallybears a hydroxy group or acetoxy group on said CH₂ group, R² ishydrogen; and n is 0 or n is 1 or 2 and an R³ group, if present, islocated at the 5- or 6-position of the benzofuran ring and is selectedfrom fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl,ethynyl, methoxy and ethoxy; or a pharmaceutically acceptableacid-addition salt thereof.
 5. A quinazoline derivative of the Formula Iaccording to claim 1 wherein: m is 2 and the first R¹ group is a6-methoxy group and the second R¹ group is located at the 7-position andis selected from 3-(N-isopropyl-N-methylamino)propoxy,3-(N-isobutyl-N-methylamino)propoxy, 3-pyrrolidin-1-ylpropoxy,3-morpholinopropoxy, 3-piperidinopropoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 3-homopiperidinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy and3-(4-cyanomethylpiperazin-1-yl)propoxy, and wherein any CH₂ group withinthe second R¹ group that is attached to two carbon atoms optionallybears a hydroxy or acetoxy group on said CH₂ group; R² is hydrogen; andn is 0 or n is 1 and the R³ group is located at the 5- or 6-position ofthe benzofuran ring and is selected from fluoro and chloro; or apharmaceutically acceptable acid-addition salt thereof.
 6. A quinazolinederivative of the Formula I according to claim 1 selected from:4-(7-benzofuranylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(7-benzofuranylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,4-(7-benzofuranylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,4-(7-benzofuranylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,4-(3-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,4-(6-chlorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,4-(5-fluorobenzofuran-7-ylamino)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(7-benzofuranylamino)-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline,7-(2-acetoxy-3-pyrrolidin-1-ylpropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,7-[2-acetoxy-3-(N-isopropyl-N-methylamino)propoxy]-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,7-[2-acetoxy-3-(4-cyanomethylpiperazin-1-yl)propoxy]-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,7-(2-acetoxy-3-piperidinopropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline,4-(3-chlorobenzofuran-7-ylamino)-7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxyquinazoline,4-(3-chlorobenzofuran-7-ylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6-methoxyquinazoline,4-(3-chlorobenzofuran-7-ylamino)-7-[3-(4-cyanomethylpiperazin-1-yl)-2-hydroxypropoxy]-6-methoxyquinazolineand4-(3-chlorobenzofuran-7-ylamino)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxyquinazoline;or a pharmaceutically acceptable acid-addition salt thereof.
 7. Aprocess for the preparation of a quinazoline derivative of the FormulaI, or a pharmaceutically-acceptable salt thereof, according to claim 1which comprises: (a) the reaction of a quinazoline of the Formula II

 wherein L is a displaceable group and m and R¹ have any of the meaningsdefined in claim 1 except that any functional group is protected ifnecessary, with an aniline of the Formula III

 wherein R², n and R³ have any of the meanings defined in claim 1 exceptthat any functional group is protected if necessary, whereafter anyprotecting group that is present is removed by conventional means; (b)for the production of those compounds of the Formula I wherein at leastone R¹ group is a group of the formulaQ¹—X¹—  wherein Q¹ is an aryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl orheterocyclyl-(1-6C)alkyl group or an optionally substituted alkyl groupand X¹ is an oxygen atom, the coupling of a quinazoline of the Formula V

 wherein m, R¹, R², n and R³ have any of the meanings defined in claim 1except that any functional group is protected if necessary, with anappropriate alcohol wherein any functional group is protected ifnecessary whereafter any protecting group that is present is removed byconventional means; (c) for the production of those compounds of theFormula I wherein an R¹ group contains a primary or secondary aminogroup, the cleavage of the corresponding compound of the Formula Iwherein the R¹ group contains a protected primary or secondary aminogroup; (d) for the production of those compounds of the Formula Iwherein an R¹ group contains a (1-6C)alkoxy or substituted (1-6C)alkoxygroup or a (1-6C)alkylamino or substituted (1-6C)alkylamino group, thealkylation of a quinazoline derivative of the formula I wherein the R¹group contains a hydroxy group or a primary or secondary amino group asappropriate; (e) for the production of those compounds of the Formula Iwherein R¹ is an amino-hydroxy-disubstituted (1-6C)alkoxy group, thereaction of a compound of the Formula I wherein the R¹ group contains anepoxy-substituted (1-6C)alkoxy group with a heterocyclyl compound or anappropriate amine; or (f) for the production of those compounds of theFormula I wherein an R¹ group contains a hydroxy group, the cleavage ofthe corresponding compound of the Formula I wherein the R¹ groupcontains a protected hydroxy group; and when a pharmaceuticallyacceptable salt of a quinazoline derivative of the Formula I is requiredit may be obtained using a conventional procedure.
 8. A pharmaceuticalcomposition which comprises a quinazoline derivative of the Formula I,or a pharmaceutically-acceptable salt thereof, as defined in claim 1 inassociation with a pharmaceutically-acceptable diluent or carrier.